rs8178225

Positions:

• chr8-47799296-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006904.7(PRKDC):​c.10211G>A​(p.Gly3404Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,624 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 32)
  • Exomes 𝑓: 0.015 (210 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056900084).
• BP6: Variant 8-47799296-C-T is Benign according to our data. Variant chr8-47799296-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1821/152284) while in subpopulation NFE AF= 0.0198 (1348/68026). AF 95% confidence interval is 0.0189. There are 20 homozygotes in gnomad4. There are 916 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.10211G>A	p.Gly3404Glu	missense_variant	72/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.10211G>A	p.Gly3404Glu	missense_variant	72/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.10211G>A	p.Gly3404Glu	missense_variant	72/86	1	NM_006904.7	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1822 AN: 152166 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0115 AC: 2866 AN: 248590 Hom.: 32 AF XY: 0.0111 AC XY: 1494 AN XY: 134872

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00527

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.00927

GnomAD4 exome AF: 0.0149 AC: 21794 AN: 1461340 Hom.: 210 Cov.: 30 AF XY: 0.0144 AC XY: 10492 AN XY: 726952

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0120 AC: 1821 AN: 152284 Hom.: 20 Cov.: 32 AF XY: 0.0123 AC XY: 916 AN XY: 74476

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0160 Hom.: 44

Bravo AF: 0.00980

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00299 AC: 12

ESP6500EA AF: 0.0194 AC: 162

ExAC AF: 0.0117 AC: 1412

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.0
DANN	Benign	0.26
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
REVEL	Benign	0.18
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.056
MPC		0.21
ClinPred		0.0024	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.059
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8178225; hg19: chr8-48711857; COSMIC: COSV58043996;