rs8178216

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/18 in silico tools predict 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. P3201P) has been classified 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

Publications

17 publications found

Variant links:

COSMIC-nc: COSV58042942

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 Gene-Disease associations (from GenCC):

severe combined immunodeficiency due to DNA-PKcs deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

PRKDC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 379755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.9601C>T	p.Pro3201Ser	missense_variant	Exon 69 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.9601C>T	p.Pro3201Ser	missense_variant	Exon 69 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 link	c.9601C>T	p.Pro3201Ser	missense_variant	Exon 69 of 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

GnomAD2 exomes

AF:

0.00647

AC:

1575

AN:

243262

AF XY:

0.00652

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 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

African (AFR)

AF:

0.00120

AC:

AN:

33254

American (AMR)

AF:

0.00173

AC:

AN:

43868

Ashkenazi Jewish (ASJ)

AF:

0.000425

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

39396

South Asian (SAS)

AF:

0.00248

AC:

210

AN:

84808

European-Finnish (FIN)

AF:

0.0114

AC:

607

AN:

53244

Middle Eastern (MID)

AF:

0.00245

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0118

AC:

13023

AN:

1107478

Other (OTH)

AF:

0.00648

AC:

389

AN:

59990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

662

1324

1986

2648

3310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00709

AC:

1080

AN:

152244

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

514

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41534

American (AMR)

AF:

0.00209

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00146

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

817

AN:

68026

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00784

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 13, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 07, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24476948) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRKDC: BP4, BS1, BS2 -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.42

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

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over