rs45438803

chr8-47929994-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006904.7(PRKDC):c.1911A>G(p.Lys637=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,604,406 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (38 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.125

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-47929994-T-C is Benign according to our data. Variant chr8-47929994-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.125 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.1911A>G	p.Lys637=	synonymous_variant	18/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.1911A>G	p.Lys637=	synonymous_variant	18/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.1911A>G	p.Lys637=	synonymous_variant	18/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.1911A>G	p.Lys637=	synonymous_variant	18/85	1

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 616 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00401 AC: 961 AN: 239736 Hom.: 2 AF XY: 0.00411 AC XY: 533 AN XY: 129754

Gnomad AFR exome AF: 0.000655

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00132

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000953

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00700

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00618 AC: 8981 AN: 1452082 Hom.: 38 Cov.: 30 AF XY: 0.00595 AC XY: 4294 AN XY: 721852

Gnomad4 AFR exome AF: 0.000939

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000866

Gnomad4 FIN exome AF: 0.00214

Gnomad4 NFE exome AF: 0.00749

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.00404 AC: 616 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74496

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00697

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00568 Hom.: 2

Bravo AF: 0.00428

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00629

EpiControl AF: 0.00607

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PRKDC: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 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. -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PRKDC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	4.6
Dann	Benign	0.61

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: rs45438803; hg19: chr8-48842554; COSMIC: COSV104628506; COSMIC: COSV104628506;