rs8178046

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000314191.7(PRKDC):c.2083C>T(p.Pro695Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,579,236 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 18 hom., cov: 32)

Exomes 𝑓: 0.015 ( 231 hom. )

Consequence

PRKDC
ENST00000314191.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.962

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030925572).

BP6

Variant 8-47929148-G-A is Benign according to our data. Variant chr8-47929148-G-A is described in ClinVar as [Benign]. Clinvar id is 379426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47929148-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1713/152292) while in subpopulation NFE AF= 0.0194 (1323/68024). AF 95% confidence interval is 0.0186. There are 18 homozygotes in gnomad4. There are 767 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.2083C>T	p.Pro695Ser	missense_variant	19/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2 linkuse as main transcript	c.2083C>T	p.Pro695Ser	missense_variant	19/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.2083C>T	p.Pro695Ser	missense_variant	19/86	1	NM_006904.7	ENSP00000313420	P1	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.2083C>T	p.Pro695Ser	missense_variant	19/85	1		ENSP00000345182		P78527-2
PRKDC	ENST00000541488.1 linkuse as main transcript	n.22C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1717

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00980

AC:

1956

AN:

199624

Hom.:

AF XY:

0.00918

AC XY:

977

AN XY:

106480

show subpopulations

Gnomad AFR exome

AF:

0.00352

Gnomad AMR exome

AF:

0.00455

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.0000668

Gnomad SAS exome

AF:

0.000318

Gnomad FIN exome

AF:

0.00584

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0100

GnomAD4 exome

AF:

0.0151

AC:

21536

AN:

1426944

Hom.:

231

Cov.:

AF XY:

0.0147

AC XY:

10352

AN XY:

706320

show subpopulations

Gnomad4 AFR exome

AF:

0.00241

Gnomad4 AMR exome

AF:

0.00515

Gnomad4 ASJ exome

AF:

0.00903

Gnomad4 EAS exome

AF:

0.0000519

Gnomad4 SAS exome

AF:

0.000504

Gnomad4 FIN exome

AF:

0.00587

Gnomad4 NFE exome

AF:

0.0183

Gnomad4 OTH exome

AF:

0.00997

GnomAD4 genome

AF:

0.0112

AC:

1713

AN:

152292

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

767

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.00752

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00462

Gnomad4 NFE

AF:

0.0194

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0172

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00329

AC:

ESP6500EA

AF:

0.0170

AC:

139

ExAC

AF:

0.00776

AC:

928

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 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. -

not provided

Benign:1

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.031

Sift

Benign

0.33

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0090

B;B

Vest4

0.079

MVP

0.58

MPC

0.17

ClinPred

0.0042

GERP RS

2.2

Varity_R

0.037

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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