rs8178087

chr8-47893227-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006904.7(PRKDC):c.3759G>A(p.Thr1253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,612,656 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1253T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (116 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (111 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.424

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=-0.68).
• BP6: Variant 8-47893227-C-T is Benign according to our data. Variant chr8-47893227-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.424 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.3759G>A	p.Thr1253=	synonymous_variant	31/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.3759G>A	p.Thr1253=	synonymous_variant	31/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.3759G>A	p.Thr1253=	synonymous_variant	31/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.3759G>A	p.Thr1253=	synonymous_variant	31/85	1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3456 AN: 152154 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00556 AC: 1316 AN: 236788 Hom.: 47 AF XY: 0.00415 AC XY: 535 AN XY: 128906

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000181

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00233 AC: 3398 AN: 1460386 Hom.: 111 Cov.: 30 AF XY: 0.00202 AC XY: 1464 AN XY: 726378

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.00397

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.00481

GnomAD4 genome AF: 0.0227 AC: 3461 AN: 152270 Hom.: 116 Cov.: 32 AF XY: 0.0213 AC XY: 1587 AN XY: 74454

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00401 Hom.: 32

Bravo AF: 0.0257

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.7
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs8178087; hg19: chr8-48805788; COSMIC: COSV104628852;