rs56047668

Positions:

• chr8-47900422-C-A
• chr8-47900422-C-T

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.3315G>T​(p.Val1105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,611,894 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.191

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=-0.65).
• BP6: Variant 8-47900422-C-A is Benign according to our data. Variant chr8-47900422-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 475225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47900422-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.3315G>T	p.Val1105=	synonymous_variant	28/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.3315G>T	p.Val1105=	synonymous_variant	28/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.3315G>T	p.Val1105=	synonymous_variant	28/86	1	NM_006904.7	ENSP00000313420	P1
PRKDC	ENST00000338368.7	c.3315G>T	p.Val1105=	synonymous_variant	28/85	1		ENSP00000345182

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00172 AC: 423 AN: 245558 Hom.: 2 AF XY: 0.00183 AC XY: 243 AN XY: 132982

Gnomad AFR exome AF: 0.000330

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00138 AC: 2013 AN: 1459584 Hom.: 5 Cov.: 30 AF XY: 0.00141 AC XY: 1021 AN XY: 725722

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00883

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74482

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000824

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

PRKDC-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 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	-0.65
CADD	Benign	4.5
DANN	Benign	0.65

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: rs56047668; hg19: chr8-48812982; COSMIC: COSV58057698;