rs587777685

Variant names:

• chr8-47820870-A-C
• rs587777685
• NM_006904.7:c.9185T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-47820870-A-C
• chr8-47820870-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.86

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]

ACMG classification

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
PRKDC	NM_006904.7	c.9185T>G	p.Leu3062Arg	missense_variant	Exon 66 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.9185T>G	p.Leu3062Arg	missense_variant	Exon 66 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.9185T>G	p.Leu3062Arg	missense_variant	Exon 66 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.9185T>G	p.Leu3062Arg	missense_variant	Exon 66 of 85	1		ENSP00000345182.4
PRKDC	ENST00000697603.1	c.1862T>G	p.Leu621Arg	missense_variant	Exon 13 of 33			ENSP00000513358.1

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

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

Other links and lift over

dbSNP: rs587777685; hg19: chr8-48733431;