Phenotypic Mutation 'screamer2' (pdf version)
Allele | screamer2 |
Mutation Type |
critical splice donor site
|
Chromosome | 16 |
Coordinate | 15,470,416 bp (GRCm39) |
Base Change | T ⇒ C (forward strand) |
Gene |
Prkdc
|
Gene Name | protein kinase, DNA activated, catalytic polypeptide |
Synonym(s) | slip, DNA-PK, XRCC7, DNAPDcs, DOXNPH, dxnph, DNA-PKcs |
Chromosomal Location |
15,455,730-15,660,099 bp (+) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.[provided by RefSeq, Jul 2010] PHENOTYPE: Mutations at this locus effect genome stability, radiation sensitivity and DNA repair. Nonsense (scid) and null homozygotes have severe combined immunodeficiency. A BALB/c variant allele reduces enzyme activity and predisposes to breast cancer. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_011159; MGI:104779
|
Mapped | Yes |
Limits of the Critical Region |
15637866 - 15842239 bp |
Amino Acid Change |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000023352 †]
† probably from a misspliced transcript
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000023352 Gene: ENSMUSG00000022672
Domain | Start | End | E-Value | Type |
low complexity region
|
125 |
138 |
N/A |
INTRINSIC |
low complexity region
|
1253 |
1263 |
N/A |
INTRINSIC |
low complexity region
|
1508 |
1522 |
N/A |
INTRINSIC |
NUC194
|
1810 |
2206 |
2.37e-246 |
SMART |
SCOP:d1gw5a_
|
2210 |
2493 |
5e-3 |
SMART |
low complexity region
|
2669 |
2681 |
N/A |
INTRINSIC |
low complexity region
|
2841 |
2855 |
N/A |
INTRINSIC |
Pfam:FAT
|
3024 |
3470 |
8.2e-75 |
PFAM |
PI3Kc
|
3749 |
4068 |
3.67e-86 |
SMART |
FATC
|
4096 |
4128 |
1.57e-9 |
SMART |
|
Predicted Effect |
probably null
|
Meta Mutation Damage Score |
0.9594 |
Is this an essential gene? |
Probably essential (E-score: 0.953) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All mutations/alleles(30) : Chemically induced (ENU)(5) Gene trapped(17) QTL(1) Spontaneous(2) Targeted(4) Transgenic(1)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00157:Prkdc
|
APN |
16 |
15515090 |
missense |
probably damaging |
1.00 |
IGL00225:Prkdc
|
APN |
16 |
15627508 |
missense |
possibly damaging |
0.64 |
IGL00481:Prkdc
|
APN |
16 |
15608330 |
missense |
probably benign |
0.41 |
IGL00488:Prkdc
|
APN |
16 |
15593711 |
splice site |
probably null |
|
IGL00489:Prkdc
|
APN |
16 |
15617790 |
missense |
possibly damaging |
0.51 |
IGL00579:Prkdc
|
APN |
16 |
15482103 |
missense |
probably damaging |
1.00 |
IGL00587:Prkdc
|
APN |
16 |
15470222 |
splice site |
probably benign |
|
IGL00666:Prkdc
|
APN |
16 |
15554699 |
missense |
probably damaging |
1.00 |
IGL00675:Prkdc
|
APN |
16 |
15605022 |
missense |
probably benign |
0.05 |
IGL00708:Prkdc
|
APN |
16 |
15597290 |
missense |
probably damaging |
0.97 |
IGL00725:Prkdc
|
APN |
16 |
15634503 |
missense |
probably benign |
0.10 |
IGL00818:Prkdc
|
APN |
16 |
15577618 |
missense |
possibly damaging |
0.92 |
IGL00917:Prkdc
|
APN |
16 |
15557428 |
missense |
probably damaging |
0.98 |
IGL00990:Prkdc
|
APN |
16 |
15519979 |
missense |
probably benign |
0.03 |
IGL01126:Prkdc
|
APN |
16 |
15487185 |
missense |
probably benign |
0.01 |
IGL01141:Prkdc
|
APN |
16 |
15544568 |
missense |
probably damaging |
0.99 |
IGL01306:Prkdc
|
APN |
16 |
15485595 |
missense |
possibly damaging |
0.67 |
IGL01326:Prkdc
|
APN |
16 |
15647556 |
missense |
probably benign |
|
IGL01335:Prkdc
|
APN |
16 |
15634760 |
critical splice donor site |
probably null |
|
IGL01419:Prkdc
|
APN |
16 |
15653030 |
missense |
probably damaging |
1.00 |
IGL01434:Prkdc
|
APN |
16 |
15531451 |
missense |
probably benign |
0.00 |
IGL01554:Prkdc
|
APN |
16 |
15470166 |
missense |
probably benign |
0.05 |
IGL01671:Prkdc
|
APN |
16 |
15485609 |
missense |
possibly damaging |
0.90 |
IGL01871:Prkdc
|
APN |
16 |
15600951 |
missense |
probably benign |
0.00 |
IGL01874:Prkdc
|
APN |
16 |
15552858 |
missense |
possibly damaging |
0.89 |
IGL01930:Prkdc
|
APN |
16 |
15516751 |
missense |
probably damaging |
1.00 |
IGL01984:Prkdc
|
APN |
16 |
15526643 |
missense |
probably benign |
|
IGL02121:Prkdc
|
APN |
16 |
15535048 |
missense |
probably benign |
0.18 |
IGL02152:Prkdc
|
APN |
16 |
15487149 |
missense |
probably benign |
0.15 |
IGL02172:Prkdc
|
APN |
16 |
15627623 |
missense |
probably benign |
0.10 |
IGL02336:Prkdc
|
APN |
16 |
15603843 |
missense |
probably benign |
0.01 |
IGL02336:Prkdc
|
APN |
16 |
15603842 |
missense |
possibly damaging |
0.47 |
IGL02393:Prkdc
|
APN |
16 |
15634622 |
missense |
probably benign |
0.42 |
IGL02406:Prkdc
|
APN |
16 |
15488399 |
missense |
probably benign |
0.00 |
IGL02500:Prkdc
|
APN |
16 |
15532146 |
critical splice donor site |
probably null |
|
IGL02568:Prkdc
|
APN |
16 |
15544406 |
missense |
probably damaging |
0.98 |
IGL02579:Prkdc
|
APN |
16 |
15488465 |
missense |
possibly damaging |
0.83 |
IGL02652:Prkdc
|
APN |
16 |
15600951 |
missense |
probably benign |
0.00 |
IGL02661:Prkdc
|
APN |
16 |
15587689 |
missense |
possibly damaging |
0.92 |
IGL02685:Prkdc
|
APN |
16 |
15653907 |
missense |
possibly damaging |
0.61 |
IGL02741:Prkdc
|
APN |
16 |
15570590 |
splice site |
probably benign |
|
IGL02803:Prkdc
|
APN |
16 |
15651530 |
splice site |
probably benign |
|
IGL02866:Prkdc
|
APN |
16 |
15649191 |
missense |
probably damaging |
1.00 |
IGL02882:Prkdc
|
APN |
16 |
15469383 |
nonsense |
probably null |
|
IGL02989:Prkdc
|
APN |
16 |
15617880 |
missense |
possibly damaging |
0.67 |
IGL03053:Prkdc
|
APN |
16 |
15652030 |
missense |
probably benign |
0.02 |
IGL03071:Prkdc
|
APN |
16 |
15617848 |
missense |
probably benign |
0.01 |
IGL03091:Prkdc
|
APN |
16 |
15523174 |
splice site |
probably benign |
|
IGL03100:Prkdc
|
APN |
16 |
15531499 |
missense |
probably benign |
0.08 |
IGL03128:Prkdc
|
APN |
16 |
15518608 |
splice site |
probably benign |
|
IGL03168:Prkdc
|
APN |
16 |
15652030 |
missense |
probably benign |
0.02 |
IGL03204:Prkdc
|
APN |
16 |
15587665 |
missense |
probably benign |
0.01 |
IGL03390:Prkdc
|
APN |
16 |
15488490 |
nonsense |
probably null |
|
anhimid
|
UTSW |
16 |
15543325 |
critical splice donor site |
probably null |
|
anhinga
|
UTSW |
16 |
15526796 |
critical splice donor site |
probably null |
|
Bushtit
|
UTSW |
16 |
15570628 |
missense |
probably damaging |
0.97 |
clover
|
UTSW |
16 |
15520020 |
splice site |
probably benign |
|
crackle
|
UTSW |
16 |
15603914 |
critical splice donor site |
probably null |
|
Daffy
|
UTSW |
16 |
15647561 |
missense |
possibly damaging |
0.86 |
darter
|
UTSW |
16 |
15591477 |
missense |
possibly damaging |
0.93 |
Elmer_fudd
|
UTSW |
16 |
15625922 |
missense |
probably benign |
0.01 |
envenomation
|
UTSW |
16 |
15653091 |
nonsense |
probably null |
|
hobgoblin
|
UTSW |
16 |
15633850 |
missense |
probably damaging |
1.00 |
Incubus
|
UTSW |
16 |
15490191 |
missense |
probably damaging |
1.00 |
liming
|
UTSW |
16 |
15570693 |
nonsense |
probably null |
|
newt
|
UTSW |
16 |
15545590 |
missense |
probably benign |
0.04 |
ornithorhynchus
|
UTSW |
16 |
15634523 |
critical splice donor site |
probably null |
|
primitive
|
UTSW |
16 |
15653022 |
frame shift |
probably null |
|
roadrunner
|
UTSW |
16 |
15651751 |
missense |
probably damaging |
1.00 |
Schreier
|
UTSW |
16 |
15488392 |
missense |
probably benign |
0.00 |
screamer
|
UTSW |
16 |
15649146 |
nonsense |
probably null |
|
Screamer10
|
UTSW |
16 |
15585889 |
missense |
probably damaging |
0.98 |
screamer3
|
UTSW |
16 |
15558196 |
critical splice donor site |
probably null |
|
screamer4
|
UTSW |
16 |
15600943 |
missense |
probably benign |
0.00 |
screamer5
|
UTSW |
16 |
15505268 |
missense |
probably benign |
|
screamer6
|
UTSW |
16 |
15577469 |
missense |
probably damaging |
1.00 |
screamer7
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
Screamer8
|
UTSW |
16 |
15537297 |
missense |
probably benign |
0.00 |
Screamer9
|
UTSW |
16 |
15552786 |
missense |
probably benign |
0.01 |
Tweetie
|
UTSW |
16 |
15535665 |
missense |
probably damaging |
1.00 |
updock
|
UTSW |
16 |
15612958 |
missense |
probably benign |
|
ANU23:Prkdc
|
UTSW |
16 |
15485595 |
missense |
possibly damaging |
0.67 |
R0008:Prkdc
|
UTSW |
16 |
15526565 |
splice site |
probably benign |
|
R0018:Prkdc
|
UTSW |
16 |
15544406 |
missense |
probably benign |
0.03 |
R0018:Prkdc
|
UTSW |
16 |
15544406 |
missense |
probably benign |
0.03 |
R0069:Prkdc
|
UTSW |
16 |
15544368 |
missense |
probably benign |
0.03 |
R0125:Prkdc
|
UTSW |
16 |
15516871 |
missense |
probably damaging |
0.98 |
R0131:Prkdc
|
UTSW |
16 |
15531517 |
missense |
probably benign |
0.09 |
R0131:Prkdc
|
UTSW |
16 |
15531517 |
missense |
probably benign |
0.09 |
R0132:Prkdc
|
UTSW |
16 |
15531517 |
missense |
probably benign |
0.09 |
R0137:Prkdc
|
UTSW |
16 |
15558196 |
critical splice donor site |
probably null |
|
R0334:Prkdc
|
UTSW |
16 |
15554663 |
missense |
probably benign |
0.00 |
R0373:Prkdc
|
UTSW |
16 |
15609791 |
missense |
probably damaging |
1.00 |
R0485:Prkdc
|
UTSW |
16 |
15651604 |
missense |
probably damaging |
0.97 |
R0511:Prkdc
|
UTSW |
16 |
15649146 |
nonsense |
probably null |
|
R0538:Prkdc
|
UTSW |
16 |
15651652 |
missense |
probably damaging |
1.00 |
R0595:Prkdc
|
UTSW |
16 |
15625952 |
missense |
probably damaging |
1.00 |
R0607:Prkdc
|
UTSW |
16 |
15589921 |
missense |
probably damaging |
0.98 |
R0616:Prkdc
|
UTSW |
16 |
15508271 |
missense |
probably damaging |
1.00 |
R0630:Prkdc
|
UTSW |
16 |
15628665 |
missense |
probably damaging |
1.00 |
R0694:Prkdc
|
UTSW |
16 |
15586501 |
missense |
probably damaging |
1.00 |
R0702:Prkdc
|
UTSW |
16 |
15603835 |
missense |
possibly damaging |
0.95 |
R0965:Prkdc
|
UTSW |
16 |
15647580 |
missense |
probably benign |
|
R1027:Prkdc
|
UTSW |
16 |
15468576 |
missense |
possibly damaging |
0.80 |
R1029:Prkdc
|
UTSW |
16 |
15472613 |
splice site |
probably benign |
|
R1033:Prkdc
|
UTSW |
16 |
15585815 |
missense |
probably damaging |
1.00 |
R1067:Prkdc
|
UTSW |
16 |
15570646 |
missense |
probably damaging |
0.99 |
R1116:Prkdc
|
UTSW |
16 |
15600943 |
missense |
probably benign |
0.00 |
R1187:Prkdc
|
UTSW |
16 |
15577610 |
missense |
probably damaging |
0.98 |
R1226:Prkdc
|
UTSW |
16 |
15491861 |
missense |
possibly damaging |
0.80 |
R1279:Prkdc
|
UTSW |
16 |
15508146 |
missense |
probably damaging |
1.00 |
R1304:Prkdc
|
UTSW |
16 |
15577587 |
missense |
probably damaging |
0.99 |
R1314:Prkdc
|
UTSW |
16 |
15482091 |
missense |
possibly damaging |
0.68 |
R1351:Prkdc
|
UTSW |
16 |
15485564 |
missense |
possibly damaging |
0.62 |
R1509:Prkdc
|
UTSW |
16 |
15549430 |
missense |
probably damaging |
1.00 |
R1512:Prkdc
|
UTSW |
16 |
15505268 |
missense |
probably benign |
|
R1531:Prkdc
|
UTSW |
16 |
15589970 |
missense |
probably benign |
0.01 |
R1579:Prkdc
|
UTSW |
16 |
15493192 |
missense |
probably benign |
0.00 |
R1669:Prkdc
|
UTSW |
16 |
15551922 |
missense |
probably damaging |
1.00 |
R1682:Prkdc
|
UTSW |
16 |
15494853 |
missense |
probably benign |
0.19 |
R1713:Prkdc
|
UTSW |
16 |
15612958 |
missense |
probably benign |
|
R1762:Prkdc
|
UTSW |
16 |
15455825 |
missense |
probably benign |
|
R1789:Prkdc
|
UTSW |
16 |
15557388 |
missense |
probably damaging |
1.00 |
R1822:Prkdc
|
UTSW |
16 |
15577469 |
missense |
probably damaging |
1.00 |
R1848:Prkdc
|
UTSW |
16 |
15625922 |
missense |
probably benign |
0.01 |
R1887:Prkdc
|
UTSW |
16 |
15647499 |
missense |
probably benign |
0.00 |
R1891:Prkdc
|
UTSW |
16 |
15543300 |
missense |
probably benign |
0.02 |
R1921:Prkdc
|
UTSW |
16 |
15532079 |
missense |
possibly damaging |
0.80 |
R1922:Prkdc
|
UTSW |
16 |
15532130 |
missense |
probably benign |
0.00 |
R1929:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R1939:Prkdc
|
UTSW |
16 |
15653777 |
missense |
possibly damaging |
0.95 |
R2021:Prkdc
|
UTSW |
16 |
15494873 |
missense |
probably benign |
0.00 |
R2033:Prkdc
|
UTSW |
16 |
15505216 |
splice site |
probably benign |
|
R2056:Prkdc
|
UTSW |
16 |
15545469 |
missense |
probably benign |
0.03 |
R2057:Prkdc
|
UTSW |
16 |
15545469 |
missense |
probably benign |
0.03 |
R2058:Prkdc
|
UTSW |
16 |
15545469 |
missense |
probably benign |
0.03 |
R2082:Prkdc
|
UTSW |
16 |
15533827 |
missense |
probably damaging |
1.00 |
R2109:Prkdc
|
UTSW |
16 |
15505254 |
missense |
probably benign |
0.01 |
R2124:Prkdc
|
UTSW |
16 |
15537297 |
missense |
probably benign |
0.00 |
R2164:Prkdc
|
UTSW |
16 |
15523071 |
missense |
probably damaging |
1.00 |
R2174:Prkdc
|
UTSW |
16 |
15552786 |
missense |
probably benign |
0.01 |
R2191:Prkdc
|
UTSW |
16 |
15516688 |
missense |
probably damaging |
1.00 |
R2270:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R2271:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R2272:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R2356:Prkdc
|
UTSW |
16 |
15502068 |
missense |
probably benign |
|
R2852:Prkdc
|
UTSW |
16 |
15470416 |
critical splice donor site |
probably null |
|
R3115:Prkdc
|
UTSW |
16 |
15482222 |
missense |
probably benign |
0.01 |
R3116:Prkdc
|
UTSW |
16 |
15482222 |
missense |
probably benign |
0.01 |
R3499:Prkdc
|
UTSW |
16 |
15585889 |
missense |
probably damaging |
0.98 |
R3687:Prkdc
|
UTSW |
16 |
15617831 |
missense |
probably benign |
|
R3834:Prkdc
|
UTSW |
16 |
15609810 |
missense |
probably damaging |
1.00 |
R3835:Prkdc
|
UTSW |
16 |
15609810 |
missense |
probably damaging |
1.00 |
R3961:Prkdc
|
UTSW |
16 |
15647475 |
splice site |
probably null |
|
R4151:Prkdc
|
UTSW |
16 |
15634637 |
missense |
probably benign |
|
R4233:Prkdc
|
UTSW |
16 |
15653783 |
missense |
probably benign |
0.11 |
R4281:Prkdc
|
UTSW |
16 |
15623963 |
splice site |
probably null |
|
R4296:Prkdc
|
UTSW |
16 |
15555769 |
missense |
probably damaging |
0.99 |
R4344:Prkdc
|
UTSW |
16 |
15585886 |
missense |
probably damaging |
0.98 |
R4424:Prkdc
|
UTSW |
16 |
15653946 |
missense |
probably damaging |
1.00 |
R4424:Prkdc
|
UTSW |
16 |
15591603 |
missense |
probably damaging |
0.98 |
R4497:Prkdc
|
UTSW |
16 |
15518517 |
missense |
probably benign |
0.43 |
R4549:Prkdc
|
UTSW |
16 |
15554734 |
missense |
possibly damaging |
0.89 |
R4594:Prkdc
|
UTSW |
16 |
15585830 |
missense |
possibly damaging |
0.64 |
R4603:Prkdc
|
UTSW |
16 |
15628688 |
missense |
probably damaging |
0.98 |
R4615:Prkdc
|
UTSW |
16 |
15480938 |
missense |
probably damaging |
0.99 |
R4648:Prkdc
|
UTSW |
16 |
15634638 |
missense |
probably benign |
0.05 |
R4662:Prkdc
|
UTSW |
16 |
15551916 |
missense |
probably damaging |
1.00 |
R4680:Prkdc
|
UTSW |
16 |
15589894 |
missense |
probably benign |
0.00 |
R4700:Prkdc
|
UTSW |
16 |
15519976 |
missense |
probably damaging |
1.00 |
R4716:Prkdc
|
UTSW |
16 |
15628701 |
missense |
probably benign |
0.32 |
R4720:Prkdc
|
UTSW |
16 |
15485579 |
missense |
probably benign |
|
R4785:Prkdc
|
UTSW |
16 |
15466840 |
missense |
probably benign |
0.21 |
R4822:Prkdc
|
UTSW |
16 |
15468576 |
missense |
possibly damaging |
0.80 |
R4829:Prkdc
|
UTSW |
16 |
15519939 |
missense |
possibly damaging |
0.80 |
R4981:Prkdc
|
UTSW |
16 |
15496173 |
missense |
probably damaging |
1.00 |
R4989:Prkdc
|
UTSW |
16 |
15491861 |
missense |
possibly damaging |
0.80 |
R5059:Prkdc
|
UTSW |
16 |
15655882 |
missense |
probably damaging |
1.00 |
R5074:Prkdc
|
UTSW |
16 |
15589912 |
missense |
probably damaging |
1.00 |
R5115:Prkdc
|
UTSW |
16 |
15608444 |
missense |
probably benign |
|
R5151:Prkdc
|
UTSW |
16 |
15533899 |
missense |
probably damaging |
1.00 |
R5165:Prkdc
|
UTSW |
16 |
15496136 |
missense |
probably damaging |
1.00 |
R5215:Prkdc
|
UTSW |
16 |
15589985 |
missense |
possibly damaging |
0.64 |
R5270:Prkdc
|
UTSW |
16 |
15552819 |
missense |
probably damaging |
1.00 |
R5278:Prkdc
|
UTSW |
16 |
15532838 |
missense |
probably damaging |
1.00 |
R5351:Prkdc
|
UTSW |
16 |
15649176 |
missense |
probably benign |
0.03 |
R5416:Prkdc
|
UTSW |
16 |
15623814 |
missense |
probably damaging |
1.00 |
R5418:Prkdc
|
UTSW |
16 |
15612961 |
missense |
probably benign |
0.20 |
R5437:Prkdc
|
UTSW |
16 |
15587739 |
missense |
possibly damaging |
0.46 |
R5452:Prkdc
|
UTSW |
16 |
15586501 |
missense |
possibly damaging |
0.96 |
R5518:Prkdc
|
UTSW |
16 |
15496172 |
missense |
probably damaging |
1.00 |
R5538:Prkdc
|
UTSW |
16 |
15469333 |
missense |
probably damaging |
1.00 |
R5589:Prkdc
|
UTSW |
16 |
15524655 |
missense |
probably benign |
0.02 |
R5618:Prkdc
|
UTSW |
16 |
15627476 |
missense |
probably damaging |
1.00 |
R5640:Prkdc
|
UTSW |
16 |
15647633 |
missense |
possibly damaging |
0.86 |
R5661:Prkdc
|
UTSW |
16 |
15628634 |
missense |
possibly damaging |
0.81 |
R5771:Prkdc
|
UTSW |
16 |
15482097 |
missense |
probably damaging |
1.00 |
R5772:Prkdc
|
UTSW |
16 |
15597252 |
missense |
possibly damaging |
0.49 |
R5783:Prkdc
|
UTSW |
16 |
15535665 |
missense |
probably damaging |
1.00 |
R5792:Prkdc
|
UTSW |
16 |
15634616 |
missense |
probably damaging |
1.00 |
R5797:Prkdc
|
UTSW |
16 |
15555698 |
nonsense |
probably null |
|
R5826:Prkdc
|
UTSW |
16 |
15551962 |
missense |
probably benign |
|
R5883:Prkdc
|
UTSW |
16 |
15533778 |
missense |
probably benign |
|
R5895:Prkdc
|
UTSW |
16 |
15570693 |
nonsense |
probably null |
|
R5998:Prkdc
|
UTSW |
16 |
15601021 |
missense |
probably damaging |
1.00 |
R6000:Prkdc
|
UTSW |
16 |
15647561 |
missense |
possibly damaging |
0.86 |
R6120:Prkdc
|
UTSW |
16 |
15557335 |
missense |
probably benign |
0.00 |
R6145:Prkdc
|
UTSW |
16 |
15589937 |
missense |
probably damaging |
1.00 |
R6209:Prkdc
|
UTSW |
16 |
15608456 |
missense |
probably damaging |
1.00 |
R6293:Prkdc
|
UTSW |
16 |
15605019 |
missense |
probably benign |
0.00 |
R6321:Prkdc
|
UTSW |
16 |
15532783 |
missense |
probably benign |
|
R6376:Prkdc
|
UTSW |
16 |
15587749 |
missense |
probably benign |
0.06 |
R6387:Prkdc
|
UTSW |
16 |
15516679 |
missense |
probably benign |
0.01 |
R6406:Prkdc
|
UTSW |
16 |
15535665 |
missense |
probably damaging |
1.00 |
R6469:Prkdc
|
UTSW |
16 |
15612939 |
missense |
probably benign |
0.10 |
R6486:Prkdc
|
UTSW |
16 |
15570628 |
missense |
probably damaging |
0.97 |
R6665:Prkdc
|
UTSW |
16 |
15603914 |
critical splice donor site |
probably null |
|
R6703:Prkdc
|
UTSW |
16 |
15488392 |
missense |
probably benign |
0.00 |
R6774:Prkdc
|
UTSW |
16 |
15543325 |
critical splice donor site |
probably null |
|
R6854:Prkdc
|
UTSW |
16 |
15469402 |
missense |
probably damaging |
1.00 |
R6878:Prkdc
|
UTSW |
16 |
15594936 |
missense |
probably benign |
0.31 |
R6882:Prkdc
|
UTSW |
16 |
15626020 |
missense |
probably benign |
0.33 |
R6882:Prkdc
|
UTSW |
16 |
15601127 |
critical splice donor site |
probably null |
|
R6949:Prkdc
|
UTSW |
16 |
15617853 |
missense |
probably benign |
|
R6950:Prkdc
|
UTSW |
16 |
15633850 |
missense |
probably damaging |
1.00 |
R7019:Prkdc
|
UTSW |
16 |
15587830 |
missense |
probably benign |
0.00 |
R7064:Prkdc
|
UTSW |
16 |
15608317 |
missense |
probably benign |
0.00 |
R7097:Prkdc
|
UTSW |
16 |
15507207 |
missense |
probably damaging |
1.00 |
R7201:Prkdc
|
UTSW |
16 |
15516667 |
missense |
probably benign |
0.12 |
R7235:Prkdc
|
UTSW |
16 |
15532127 |
missense |
probably benign |
|
R7283:Prkdc
|
UTSW |
16 |
15535628 |
missense |
probably benign |
0.00 |
R7401:Prkdc
|
UTSW |
16 |
15466602 |
missense |
probably damaging |
1.00 |
R7525:Prkdc
|
UTSW |
16 |
15490191 |
missense |
probably damaging |
1.00 |
R7647:Prkdc
|
UTSW |
16 |
15555807 |
missense |
probably damaging |
1.00 |
R7679:Prkdc
|
UTSW |
16 |
15649183 |
missense |
probably damaging |
1.00 |
R7803:Prkdc
|
UTSW |
16 |
15623960 |
missense |
probably null |
0.05 |
R7858:Prkdc
|
UTSW |
16 |
15507141 |
missense |
probably benign |
0.11 |
R7872:Prkdc
|
UTSW |
16 |
15532870 |
missense |
probably benign |
0.05 |
R7896:Prkdc
|
UTSW |
16 |
15526767 |
missense |
probably damaging |
0.97 |
R8032:Prkdc
|
UTSW |
16 |
15597315 |
missense |
probably benign |
0.00 |
R8055:Prkdc
|
UTSW |
16 |
15634749 |
missense |
probably benign |
0.09 |
R8153:Prkdc
|
UTSW |
16 |
15482108 |
missense |
probably damaging |
1.00 |
R8281:Prkdc
|
UTSW |
16 |
15523117 |
missense |
probably damaging |
1.00 |
R8302:Prkdc
|
UTSW |
16 |
15653946 |
missense |
probably damaging |
1.00 |
R8322:Prkdc
|
UTSW |
16 |
15532005 |
splice site |
probably benign |
|
R8401:Prkdc
|
UTSW |
16 |
15591477 |
missense |
possibly damaging |
0.93 |
R8440:Prkdc
|
UTSW |
16 |
15653022 |
frame shift |
probably null |
|
R8458:Prkdc
|
UTSW |
16 |
15608540 |
critical splice donor site |
probably null |
|
R8472:Prkdc
|
UTSW |
16 |
15469400 |
missense |
probably damaging |
1.00 |
R8478:Prkdc
|
UTSW |
16 |
15466788 |
missense |
probably benign |
0.00 |
R8515:Prkdc
|
UTSW |
16 |
15482232 |
missense |
probably damaging |
1.00 |
R8546:Prkdc
|
UTSW |
16 |
15480899 |
missense |
probably damaging |
1.00 |
R8678:Prkdc
|
UTSW |
16 |
15526796 |
critical splice donor site |
probably null |
|
R8739:Prkdc
|
UTSW |
16 |
15626068 |
missense |
probably benign |
0.01 |
R8749:Prkdc
|
UTSW |
16 |
15601029 |
missense |
possibly damaging |
0.85 |
R8836:Prkdc
|
UTSW |
16 |
15545523 |
missense |
probably damaging |
1.00 |
R8904:Prkdc
|
UTSW |
16 |
15545590 |
missense |
probably benign |
0.04 |
R8952:Prkdc
|
UTSW |
16 |
15491624 |
intron |
probably benign |
|
R8971:Prkdc
|
UTSW |
16 |
15493229 |
missense |
probably null |
0.99 |
R8974:Prkdc
|
UTSW |
16 |
15617726 |
splice site |
probably null |
|
R9052:Prkdc
|
UTSW |
16 |
15508160 |
missense |
probably benign |
0.05 |
R9069:Prkdc
|
UTSW |
16 |
15653091 |
nonsense |
probably null |
|
R9200:Prkdc
|
UTSW |
16 |
15523153 |
missense |
probably damaging |
1.00 |
R9235:Prkdc
|
UTSW |
16 |
15651751 |
missense |
probably damaging |
1.00 |
R9278:Prkdc
|
UTSW |
16 |
15634523 |
critical splice donor site |
probably null |
|
R9309:Prkdc
|
UTSW |
16 |
15526792 |
nonsense |
probably null |
|
R9386:Prkdc
|
UTSW |
16 |
15496136 |
missense |
probably damaging |
0.99 |
R9452:Prkdc
|
UTSW |
16 |
15485465 |
missense |
possibly damaging |
0.90 |
R9500:Prkdc
|
UTSW |
16 |
15657079 |
missense |
possibly damaging |
0.76 |
R9608:Prkdc
|
UTSW |
16 |
15548335 |
missense |
probably damaging |
1.00 |
R9608:Prkdc
|
UTSW |
16 |
15548334 |
missense |
possibly damaging |
0.96 |
R9636:Prkdc
|
UTSW |
16 |
15548341 |
missense |
probably benign |
0.19 |
R9656:Prkdc
|
UTSW |
16 |
15617818 |
missense |
probably benign |
0.00 |
R9674:Prkdc
|
UTSW |
16 |
15533819 |
missense |
probably damaging |
0.98 |
R9760:Prkdc
|
UTSW |
16 |
15657044 |
nonsense |
probably null |
|
X0023:Prkdc
|
UTSW |
16 |
15558142 |
missense |
probably benign |
|
Z1176:Prkdc
|
UTSW |
16 |
15505286 |
nonsense |
probably null |
|
|
Mode of Inheritance |
Autosomal Recessive |
Local Stock | |
MMRRC Submission |
038211-MU
|
Last Updated |
2019-09-04 9:44 PM
by Diantha La Vine
|
Record Created |
2015-08-20 9:22 PM
by Jin Huk Choi
|
Record Posted |
2015-08-25 |
Phenotypic Description |
The screamer2 phenotype among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R2852, some of which showed a diminished T-dependent antibody response to ovalbumin (OVA) administered with aluminum hydroxide (Figure 1) as well as a diminished T-dependent antibody response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 2). The T-independent antibody response to 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) was also reduced (Figure 3).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 45 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Prkdc: a T to C transition at base pair 15,652,552 (v38) on chromosome 16, or base pair 15,109 in the NC_000082 GenBank genomic region. The strongest association was found with a recessive model of linkage to the normalized T-independent antibody response to NP-Ficoll (P = 1.24 x 10-14), wherein 5 variant homozygotes departed phenotypically from 6 homozygous reference mice and 7 heterozygous mice (Figure 4). The mutation is located within the donor splice site of intron 7, two nucleotides from the previous exon. Prkdc contains 86 total exons. The effect of the mutation at the cDNA and protein level is unknown. One possibility, shown below, is that aberrant splicing may result in skipping of the 100 base pair exon 7 and out-of-frame splicing from exon 6 to exon 8. This would result in deletion of amino acids 208-241 of the DNA-PKCS protein, coding of 21 aberrant amino acids (amino acids 208-228), and coding of a premature stop codon after amino acid 228.
<--exon 6 <--exon 7 intron 7--> exon 8--> <--exon 9
14897 ……CTTAAGACCCAG……TCCATGGAAGAAG gtactgccaggct……ATCCCCAGACTT……AGATTGAGATGA 17376
204 ……-L--K--T--Q-……-S--M--E--E-- -I--P--R--L-……-R--L--R--*- 228
correct deleted aberrant
|
The donor splice site of intron 7, which is destroyed by the mutation, is indicated in blue; the mutated nucleotide is indicated in red.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
The 12,674 base pair Prkdc transcript encodes the 4,128 amino acid, 471 kDa catalytic subunit of the DNA-PK complex, DNA-PKCS. DNA-PKCS is a serine/threonine kinase and member of the phosphatidylinositol 3-kinase-like kinases (PIKK) family (see worker) [reviewed in (1)]. DNA-PKCS has several domains that are essential for its function (Figure 5). A leucine rich region (LRR, aa 1501-1536) mediates the association of DNA-PKCS with C1D, a DNA-binding nuclear matrix-associated factor. The LRR facilitates the intrinsic binding of DNA-PKCS to DNA (2). The DNA-PKCS protein also contains three tetratricopeptide repeats (TPR) (aa 1720-1753, 2921-2954, 2956-2983) that are proposed to assist in protein-protein interactions. A 380 amino acid region at the C-terminus of DNA-PKCS constitutes the catalytic domain, designated the PIKK domain (aa 3747-4015) (3). The PIKK domain is flanked by the FAT domain (named for its homology to FRAP, ATM and TRRAP, aa 2884-3539) and a FATC domain (FAT at the extreme C-terminus, aa 4096-4128) (3). The FAT and FATC domains occur in combination in all PIKK family members. The C-terminal region containing the FATC domain is essential for the kinase activity of DNA-PKCS (4-6). The N-terminal portion of the protein up to the FAT domain consists of HEAT (Huntingtin, Elongation factor 3, A subunit of protein phosphatase 2A and TOR1) repeats (amino acids 288-323, 1001-1037, and 1050-1086) (7). HEAT repeats are helical structural repeats that mediate protein-protein interactions (8). The screamer2 mutation affects the splice donor site within intron 7, and is predicted to cause skipping of exon 7. A transcript lacking exon 29 would encode the wild type sequence up to amino acid 207, followed by 21 aberrant amino acids and a premature stop. This transcript would likely be subject to nonsense-mediated decay. Please see the record clover for information about Prkdc.
|
Putative Mechanism | DNA-PKCS is the catalytic subunit of the DNA-PK complex and is essential for DNA double-strand break repair during nonhomologous end joining (NHEJ) and during the assembly of immune receptor genes (i.e., V(D)J recombination) in developing lymphocytes. Mutations in Prkdc are linked to severe combined immunodeficiency (SCID) in several animal models, a condition marked by lymphopenia, hypogammaglobulinemia, and impaired T and B cell-mediated functions (e.g. defective V(D)J recombination and reduced numbers of peripheral lymphocytes) (9-11). Mutations in Prkdc also exhibit uncapped telomeres and a large number of telomeric fusions, leading to genomic instability (9;12;13). In a spontaneous mouse model of SCID, a DNA-PKCS point mutation resulting in the loss of 83 C-terminal amino acids, a reduction in protein expression, and a block in lymphocyte development has been identified (14). The deficiency in the T-dependent antibody response to OVA-aluminum hydroxide in the screamer2 mice indicates a loss of function in DNA-PKCSscreamer2.
|
Primers |
PCR Primer
screamer2_pcr_F: TCTGGGAGAACTTAAGACCCAG
screamer2_pcr_R: ATCCCTCTTAAGTGCATAGCC
Sequencing Primer
screamer2_seq_F: GACCCAGGTATAATACTCCCTATG
screamer2_seq_R: AGCTCCTGGAGACTTGCATTCTG
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 640 nucleotides is amplified (chromosome 16, + strand):
1 tctgggagaa cttaagaccc aggtataata ctccctatga aaatatactt cctcagtctt 61 gttttcgttt ttattgtcgt tgttttcatt ttgtaatatc ttcctaaaat ctccctttta 121 gatgacatcc acagtaagag aacctaaatt tcctgtctta gctggctgtc tgaagggact 181 atcctcactt ctgtgcaact tcactaagtc catggaagaa ggtactgcca ggctttgctt 241 gattttcttt ctaataataa gaccttatct caaagataaa ataaggacaa attcggatgt 301 gtgctataat cctaatgata tgctcagtga aataagccag tccccaaaca aaaaacaagc 361 tgtatatggc tctacttgaa tgagttacat gagtaggaaa ctgtagagac agacagcaga 421 atgcaagtct ccaggagctg ggggacgggt ggtttcagtg ttgtgtatga cgaaaaagtt 481 ttaggcatgg aacatgctgt tatataacaa tgtgaaacta tttcatgcta ctaaactatg 541 tcattctaca tttttaaagt gatgaatatt atgcagattt taccacatta aaaatagatg 601 tgaggatgtt tgtttagaag gctatgcact taagagggat
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
3. Rivera-Calzada, A., Maman, J. D., Spagnolo, L., Pearl, L. H., and Llorca, O. (2005) Three-Dimensional Structure and Regulation of the DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs). Structure. 13, 243-255.
4. Jiang, X., Sun, Y., Chen, S., Roy, K., and Price, B. D. (2006) The FATC Domains of PIKK Proteins are Functionally Equivalent and Participate in the Tip60-Dependent Activation of DNA-PKcs and ATM. J Biol Chem. 281, 15741-15746.
5. Beamish, H. J., Jessberger, R., Riballo, E., Priestley, A., Blunt, T., Kysela, B., and Jeggo, P. A. (2000) The C-Terminal Conserved Domain of DNA-PKcs, Missing in the SCID Mouse, is Required for Kinase Activity. Nucleic Acids Res. 28, 1506-1513.
6. Priestley, A., Beamish, H. J., Gell, D., Amatucci, A. G., Muhlmann-Diaz, M. C., Singleton, B. K., Smith, G. C., Blunt, T., Schalkwyk, L. C., Bedford, J. S., Jackson, S. P., Jeggo, P. A., and Taccioli, G. E. (1998) Molecular and Biochemical Characterisation of DNA-Dependent Protein Kinase-Defective Rodent Mutant Irs-20. Nucleic Acids Res. 26, 1965-1973.
12. Espejel, S., Franco, S., Sgura, A., Gae, D., Bailey, S. M., Taccioli, G. E., and Blasco, M. A. (2002) Functional Interaction between DNA-PKcs and Telomerase in Telomere Length Maintenance. EMBO J. 21, 6275-6287.
13. Williams, E. S., Klingler, R., Ponnaiya, B., Hardt, T., Schrock, E., Lees-Miller, S. P., Meek, K., Ullrich, R. L., and Bailey, S. M. (2009) Telomere Dysfunction and DNA-PKcs Deficiency: Characterization and Consequence. Cancer Res. 69, 2100-2107.
14. Danska, J. S., Holland, D. P., Mariathasan, S., Williams, K. M., and Guidos, C. J. (1996) Biochemical and Genetic Defects in the DNA-Dependent Protein Kinase in Murine Scid Lymphocytes. Mol Cell Biol. 16, 5507-5517.
|
Science Writers | Anne Murray |
Illustrators | Peter Jurek, Katherine Timer |
Authors | Jin Huk Choi, James Butler, Bruce Beutler |