rs8178249

Positions:

• chr8-47778507-G-A

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.11805C>T​(p.Gly3935Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,613,570 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (49 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.33

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]

PRKDC (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-47778507-G-A is Benign according to our data. Variant chr8-47778507-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 379753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47778507-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00534 (7805/1461262) while in subpopulation MID AF= 0.0323 (186/5766). AF 95% confidence interval is 0.0285. There are 49 homozygotes in gnomad4_exome. There are 3825 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.11805C>T	p.Gly3935Gly	synonymous_variant	83/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.11712C>T	p.Gly3904Gly	synonymous_variant	82/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.11805C>T	p.Gly3935Gly	synonymous_variant	83/86	1	NM_006904.7	ENSP00000313420.3

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152190 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00664

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00533 AC: 1323 AN: 248176 Hom.: 10 AF XY: 0.00524 AC XY: 706 AN XY: 134644

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00384

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000854

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00599

Gnomad OTH exome AF: 0.00580

GnomAD4 exome AF: 0.00534 AC: 7805 AN: 1461262 Hom.: 49 Cov.: 31 AF XY: 0.00526 AC XY: 3825 AN XY: 726852

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00900

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000987

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.00527

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00560 AC: 853 AN: 152308 Hom.: 8 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74468

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0151

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00599 Hom.: 11

Bravo AF: 0.00483

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PRKDC: BP4, BP7, BS2 -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2017

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
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.23
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8178249; hg19: chr8-48691068; COSMIC: COSV100040225; COSMIC: COSV100040225;