rs587777685

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_006904.7(PRKDC):​c.9185T>G​(p.Leu3062Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PRKDC
NM_006904.7 missense

Scores

8
5
4

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.86
Variant links:
Genes affected
PRKDC (HGNC:9413): (protein kinase, DNA-activated, catalytic subunit) 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903
PP5
Variant 8-47820870-A-C is Pathogenic according to our data. Variant chr8-47820870-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 154322.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKDCNM_006904.7 linkc.9185T>G p.Leu3062Arg missense_variant Exon 66 of 86 ENST00000314191.7 NP_008835.5 P78527-1
PRKDCNM_001081640.2 linkc.9185T>G p.Leu3062Arg missense_variant Exon 66 of 85 NP_001075109.1 P78527-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKDCENST00000314191.7 linkc.9185T>G p.Leu3062Arg missense_variant Exon 66 of 86 1 NM_006904.7 ENSP00000313420.3 P78527-1
PRKDCENST00000338368.7 linkc.9185T>G p.Leu3062Arg missense_variant Exon 66 of 85 1 ENSP00000345182.4 P78527-2
PRKDCENST00000697603.1 linkc.1862T>G p.Leu621Arg missense_variant Exon 13 of 33 ENSP00000513358.1 A0A8V8TMR1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Immunodeficiency 26 without neurologic abnormalities Pathogenic:1
Jan 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Severe combined immunodeficiency due to DNA-PKcs deficiency Pathogenic:1
Oct 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 154322). This variant is also known as c.9239T>G (p.Leu3061Arg). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 19075392, 25842288, 30121298). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3062 of the PRKDC protein (p.Leu3062Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.029
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Uncertain
0.67
T
REVEL
Uncertain
0.59
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.94
MutPred
0.71
Loss of stability (P = 0.0417);Loss of stability (P = 0.0417);
MVP
0.97
MPC
0.84
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.56
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777685; hg19: chr8-48733431; API