rs8178216

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006904.7(PRKDC):c.9601C>T(p.Pro3201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,605,872 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 89 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.419

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.005528927).

BP6

Variant 8-47807283-G-A is Benign according to our data. Variant chr8-47807283-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 379755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47807283-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.9601C>T	p.Pro3201Ser	missense_variant	69/86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 linkuse as main transcript	c.9601C>T	p.Pro3201Ser	missense_variant	69/85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.9601C>T	p.Pro3201Ser	missense_variant	69/86	1	NM_006904.7	ENSP00000313420.3		P78527-1

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

1080

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00647

AC:

1575

AN:

243262

Hom.:

AF XY:

0.00652

AC XY:

861

AN XY:

132042

show subpopulations

Gnomad AFR exome

AF:

0.00249

Gnomad AMR exome

AF:

0.00196

Gnomad ASJ exome

AF:

0.000508

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00249

Gnomad FIN exome

AF:

0.00975

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00410

GnomAD4 exome

AF:

0.00989

AC:

14370

AN:

1453628

Hom.:

Cov.:

AF XY:

0.00954

AC XY:

6897

AN XY:

722662

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00173

Gnomad4 ASJ exome

AF:

0.000425

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00248

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.00648

GnomAD4 genome

AF:

0.00709

AC:

1080

AN:

152244

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

514

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00855

Hom.:

Bravo

AF:

0.00588

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00107

AC:

ESP6500EA

AF:

0.0136

AC:

112

ExAC

AF:

0.00667

AC:

806

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2022	Variant summary: PRKDC c.9598C>T (p.Pro3200Ser) (refseq HGVS c.9601C>T, p.Pro3201Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 243262 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKDC causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is benign. To our knowledge, no penetrant association or occurrence of c.9598C>T in individuals affected with Severe Combined Immunodeficiency (specifically Immunodeficiency 26, with or without neurologic abnormalities, OMIM 60089) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PRKDC: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2018	This variant is associated with the following publications: (PMID: 24476948) -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.24

DANN

Benign

0.51

DEOGEN2

Benign

0.042

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

L;L

PrimateAI

Benign

0.22

REVEL

Benign

0.072

Sift4G

Benign

0.56

T;T

Polyphen

0.0030

B;.

Vest4

0.035

MVP

0.41

MPC

0.17

ClinPred

0.00098

GERP RS

-2.2

Varity_R

0.023

gMVP

0.087

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

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