8-47817561-C-T

Position:

chr8-47817561-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_006904.7(PRKDC):c.9446G>A(p.Gly3149Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,576,712 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 55 hom. )

Consequence

PRKDC
NM_006904.7 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.35

Variant links:

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 links:

PRKDC (HGNC:):

PRKDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 8-47817561-C-T is Benign according to our data. Variant chr8-47817561-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47817561-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00387 (589/152154) while in subpopulation SAS AF= 0.0251 (121/4820). AF 95% confidence interval is 0.0215. There are 4 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 linkuse as main transcript	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/86	1	NM_006904.7	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/85	1		ENSP00000345182.4	P78527-2
PRKDC	ENST00000697603.1 linkuse as main transcript	c.2123G>A	p.Gly708Asp	missense_variant, splice_region_variant	15/33			ENSP00000513358.1	A0A8V8TMR1
PRKDC	ENST00000697607.1 linkuse as main transcript	n.978G>A		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes

AF:

0.00385

AC:

586

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00440

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00290

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00519

AC:

1114

AN:

214792

Hom.:

AF XY:

0.00625

AC XY:

720

AN XY:

115268

show subpopulations

Gnomad AFR exome

AF:

0.00450

Gnomad AMR exome

AF:

0.00297

Gnomad ASJ exome

AF:

0.00573

Gnomad EAS exome

AF:

0.0000629

Gnomad SAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00308

Gnomad OTH exome

AF:

0.00785

GnomAD4 exome

AF:

0.00374

AC:

5329

AN:

1424558

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

3078

AN XY:

707490

show subpopulations

Gnomad4 AFR exome

AF:

0.00434

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.00590

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.0248

Gnomad4 FIN exome

AF:

0.0000573

Gnomad4 NFE exome

AF:

0.00223

Gnomad4 OTH exome

AF:

0.00531

GnomAD4 genome

AF:

0.00387

AC:

589

AN:

152154

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00441

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0251

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00290

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00346

Hom.:

Bravo

AF:

0.00348

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00467

AC:

ESP6500EA

AF:

0.00306

AC:

ExAC

AF:

0.00486

AC:

585

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.077

T;.

Eigen

Benign

-0.084

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.48

REVEL

Benign

0.14

Sift4G

Benign

0.18

T;T

Polyphen

0.029

B;.

Vest4

0.17

MVP

0.47

MPC

0.26

ClinPred

0.012

GERP RS

5.7

Varity_R

0.28

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over