Phenotypic Mutation 'screamer4' (pdf version)
Allele | screamer4 |
Mutation Type |
missense
|
Chromosome | 16 |
Coordinate | 15,600,943 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 |
Aspartic acid changed to Glycine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000023352]
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000023352 Gene: ENSMUSG00000022672 AA Change: D2868G
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 benign
PolyPhen 2
Score 0.001 (Sensitivity: 0.99; Specificity: 0.15)
(Using ENSMUST00000023352)
|
Meta Mutation Damage Score |
0.0898 |
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(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 |
|
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 | |
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 screamer4 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1116, some of which showed increased frequencies of CD44+ T cells (Figure 1) and CD44+ CD4 T cells (Figure 2) after mouse cytomegalovirus infection.
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 50 mutations. Both of the above anomalies were linked by continuous variable mapping to a mutation in Prkdc: an A to G transition at base pair 15,783,079 (v38) on chromosome 16, or base pair 145,637 in the GenBank genomic region NC_000082 encoding Prkdc. The strongest association was found with a recessive model of linkage to the normalized frequency of CD44+ T cells, wherein one variant homozygote departed phenotypically from 19 homozygous reference mice and 20 heterozygous mice with a P value of 1.36 x 10-4 (Figure 3). A semidominant effect was observed in the CD44+ CD4 T cell assay (P = 9.58 x 10-4). The mutation corresponds to residue 8626 in the mRNA sequence NM_011159 within exon 63 of 86 total exons.
8610 AGTTGCCAACACCCAGACTTCCTGACACTTGAC
2863 -S--C--Q--H--P--D--F--L--T--L--D-
|
The mutated nucleotide is indicated in red. The mutation results in an aspartic acid (D) to glycine (G) substitution at position 2868 (D2868G) in the DNA-PKCS protein, and is strongly predicted by PolyPhen-2 to be benign (score = 0.001).
|
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 4). 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 screamer4 mutation results in an aspartic acid (D) to glycine (G) substitution at position 2,868 (D2868G). Amino acid 2,868 is within an undefined region preceeding the FATC domain. 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 screamer4 mice indicates a loss of function in DNA-PKCSscreamer4.
|
Primers |
PCR Primer
screamer4_pcr_F: TGCACAGACACTTTGTAATATCACTGCC
screamer4_pcr_R: CTGTCCGCCTTCATGTTCTGGTTAA
Sequencing Primer
screamer4_seq_F: CACTGCCTATTATTACAAGTCGG
screamer4_seq_R: tgcctgtgtgtctatctgtc
|
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 476 nucleotides is amplified (chromosome 16, + strand):
1 tgcacagaca ctttgtaata tcactgccta ttattacaag tcggttgttt ttcttatgtt 61 taattaaatg gaataatcct ttgtgatgat gtcatccaaa tcctatgtgc taaacagcta 121 tatgtggttt tataggaaat aagttgccaa cacccagact tcctgacact tgacccagcc 181 tcagttcgag tgggatgcct ggctagtctg cagcagccgg gaggtatccg tcttctggaa 241 gaggccctac tccggctgat gcccaaggaa ccacccacca aaagagttcg gggcaagact 301 tgcttgcctc ccgatgttct ccggtggatg gaacttgcta agtaagtctg gggtggacca 361 ctctttgatg aacagtaagt caatcaaagt agcacaataa aatattgcct ttattttatg 421 aagacatgag ttggtaaaga ggctggagag atggctcagt agttagaaga atttgc
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 and Bruce Beutler |