rs6992074

chr8-47879638-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006904.7(PRKDC):c.5088T>G(p.Leu1696=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,583,438 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.935

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 8-47879638-A-C is Benign according to our data. Variant chr8-47879638-A-C is described in ClinVar as [Benign]. Clinvar id is 379439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.935 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1691/152218) while in subpopulation AFR AF= 0.0378 (1568/41516). AF 95% confidence interval is 0.0362. There are 43 homozygotes in gnomad4. There are 790 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.5088T>G	p.Leu1696=	synonymous_variant	39/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.5088T>G	p.Leu1696=	synonymous_variant	39/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.5088T>G	p.Leu1696=	synonymous_variant	39/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.5088T>G	p.Leu1696=	synonymous_variant	39/85	1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1676 AN: 152100 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00294 AC: 615 AN: 208936 Hom.: 11 AF XY: 0.00205 AC XY: 231 AN XY: 112610

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00165

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00123 AC: 1762 AN: 1431220 Hom.: 36 Cov.: 31 AF XY: 0.00105 AC XY: 746 AN XY: 709328

Gnomad4 AFR exome AF: 0.0390

Gnomad4 AMR exome AF: 0.00303

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000165

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.0111 AC: 1691 AN: 152218 Hom.: 43 Cov.: 32 AF XY: 0.0106 AC XY: 790 AN XY: 74436

Gnomad4 AFR AF: 0.0378

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00214 Hom.: 8

Bravo AF: 0.0124

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 26, 2016

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. -

Severe combined immunodeficiency due to DNA-PKcs deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	3.2
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs6992074; hg19: chr8-48792199; COSMIC: COSV104628858;