Phenotypic Mutation 'screamer7' (pdf version)
Allele | screamer7 |
Mutation Type |
splice site
(4 bp from exon)
|
Chromosome | 16 |
Coordinate | 15,472,681 bp (GRCm39) |
Base Change | A ⇒ G (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 |
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 |
0.9755 |
Is this an essential gene? |
Probably essential (E-score: 0.953) |
Phenotypic Category |
Autosomal Semidominant |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All mutations/alleles(32) : Chemically induced (ENU)(6) Gene trapped(17) QTL(1) Spontaneous(2) Targeted(5) 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 |
screamer2
|
UTSW |
16 |
15470416 |
critical splice donor site |
probably null |
|
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 |
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 Semidominant |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:41 PM
by Diantha La Vine
|
Record Created |
2016-12-22 9:03 AM
|
Record Posted |
2017-01-05 |
Phenotypic Description |
The Screamer7 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1929, some of which showed an increased frequency of CD44+ CD4 T cells (Figure 1) in the peripheral blood. Some mice also showed a decreased frequency of CD8+ T cells (Figure 2) and an increased frequency of plasmacytoid dendritic cells (Figure 3) in the peripheral blood after mouse cytomegalovirus (MCMV) infection.
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 108 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Prkdc: an A to G transition at base pair 15,654,817 (v38) on chromosome 16, or base pair 17,364 in the GenBank genomic region NC_000082 within the splice acceptor site on intron 8 in Prkdc. The strongest association was found with an additive model of inheritance to the diminished frequency of CD8+ T cells after MCMV infection, wherein two variant homozygotes departed phenotypically from four homozygous reference mice and seven heterozygous mice with a P value of 3.281 x 10-6 (Figure 4). The effect of the mutation at the cDNA and protein levels have not examined, but the mutation is predicted to result in the use of a cryptic splice site in intron 8. The resulting transcript would have a 3-base pair insertion of intron 8, leading to an in-frame protein product beginning after amino acid 259 in encoded protein, which is normally 4,128 amino acids long.
<--exon 8 <--intron 8--> exon 9--> <--exon 86
17284 ……ATTCGTCCTCAG gtagtattaacatt……ttttttctgcaatag ATTGAGATGAAG…………CCCTGGATGTAA…… 204522
256 ……-I--R--P--Q- -I--E--M--K-…………-P--W--M--*- 4129
correct correct
|
Genomic numbering corresponds to NC_000082. The acceptor splice site of intron 8, which is destroyed by the Screamer7 mutation, is indicated in blue lettering and 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 constitutes the catalytic domain, designated the PIKK domain, of DNA-PKCS (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 Screamer7 mutation is predicted to result in a 3-base pair insertion of intron 8, leading to an in-frame protein product beginning after amino acid 259 in encoded protein. The mutation is predicted to affect an region with no defined domains that precedes the first HEAT repeat. 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 phenotypes in the Screamer7 mice indicate a loss of function in DNA-PKCSScreamer7.
|
Primers |
PCR Primer
screamer7_pcr_F: AGCTGACACTTGCAAGTATCTG
screamer7_pcr_R: CCCAGTAAGACTTTATGTGCTTC
Sequencing Primer
screamer7_seq_F: ACACTTGCAAGTATCTGATAAATAGC
screamer7_seq_R: CAAAACCTTACTCATGATGCTA
|
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 428 nucleotides is amplified (chromosome 16, + strand):
1 agctgacact tgcaagtatc tgataaatag cataaataat gttcaattca gttttacaat 61 ttttaacggc cttctgttgt tatattctca gatccccaga cttcaaagga aatttttggt 121 tttacattta aagcaattcg tcctcaggta gtattaacat tactcttaag tcttttacag 181 ttgtacttgt gatttttcag tctatgatgg tttctttttt tctgcaatag attgagatga 241 agcgatatgc tgtgccctta ggtaagattc tgtttttaat aaggtaacag tttaaactac 301 ttaagttagc atcatgagta aggttttgtt taagtaagag tgaaagcaaa tacaaaagta 361 ttcactcata gctatttata atggagcttt aagattttat tgattgaagc acataaagtc 421 ttactggg
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 | Katherine Timer |
Authors | Tao Yue, Xue Zhong, and Bruce Beutler |