chr8-47826744-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006904.7(PRKDC):c.8695C>T(p.Arg2899Cys) variant causes a missense change. The variant allele was found at a frequency of 0.044 in 1,612,892 control chromosomes in the GnomAD database, including 1,811 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2899H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 105 hom., cov: 33)

Exomes 𝑓: 0.045 ( 1706 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.22

Publications

18 publications found

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 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002094835).

BP6

Variant 8-47826744-G-A is Benign according to our data. Variant chr8-47826744-G-A is described in ClinVar as Benign. ClinVar VariationId is 379649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.8695C>T	p.Arg2899Cys	missense_variant	Exon 63 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.8695C>T	p.Arg2899Cys	missense_variant	Exon 63 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRKDC	ENST00000314191.7 link	c.8695C>T	p.Arg2899Cys	missense_variant	Exon 63 of 86	1	NM_006904.7	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7 link	c.8695C>T	p.Arg2899Cys	missense_variant	Exon 63 of 85	1		ENSP00000345182.4	P78527-2
PRKDC	ENST00000697603.1 link	c.1372C>T	p.Arg458Cys	missense_variant	Exon 10 of 33			ENSP00000513358.1	A0A8V8TMR1

Frequencies

GnomAD3 genomes

AF:

0.0345

AC:

5248

AN:

152168

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00864

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0376

Gnomad ASJ

AF:

0.0855

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.0461

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0402

GnomAD2 exomes

AF:

0.0383

AC:

9421

AN:

245970

AF XY:

0.0381

show subpopulations

Gnomad AFR exome

AF:

0.00765

Gnomad AMR exome

AF:

0.0256

Gnomad ASJ exome

AF:

0.0896

Gnomad EAS exome

AF:

0.000448

Gnomad FIN exome

AF:

0.0472

Gnomad NFE exome

AF:

0.0547

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0450

AC:

65714

AN:

1460606

Hom.:

1706

Cov.:

AF XY:

0.0437

AC XY:

31775

AN XY:

726558

show subpopulations

African (AFR)

AF:

0.00828

AC:

277

AN:

33460

American (AMR)

AF:

0.0266

AC:

1188

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0920

AC:

2399

AN:

26088

East Asian (EAS)

AF:

0.000302

AC:

AN:

39678

South Asian (SAS)

AF:

0.00579

AC:

498

AN:

86060

European-Finnish (FIN)

AF:

0.0484

AC:

2573

AN:

53212

Middle Eastern (MID)

AF:

0.0492

AC:

275

AN:

5592

European-Non Finnish (NFE)

AF:

0.0504

AC:

55981

AN:

1111588

Other (OTH)

AF:

0.0417

AC:

2511

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3782

7564

11345

15127

18909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2026

4052

6078

8104

10130

<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:

0.0344

AC:

5242

AN:

152286

Hom.:

105

Cov.:

AF XY:

0.0334

AC XY:

2485

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00861

AC:

358

AN:

41562

American (AMR)

AF:

0.0375

AC:

574

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0855

AC:

297

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.00766

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0461

AC:

489

AN:

10604

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3386

AN:

68014

Other (OTH)

AF:

0.0398

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

273

547

820

1094

1367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0464

Hom.:

104

Bravo

AF:

0.0340

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0516

AC:

199

ESP6500AA

AF:

0.00757

AC:

ESP6500EA

AF:

0.0489

AC:

411

ExAC

AF:

0.0389

AC:

4709

Asia WGS

AF:

0.00404

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

Mar 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Benign:1

Feb 03, 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

0.079

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.082

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

L;L

PhyloP100

4.2

PrimateAI

Benign

0.23

REVEL

Benign

0.11

Sift4G

Uncertain

0.013

D;D

Polyphen

0.93

P;.

Vest4

0.065

MPC

0.23

ClinPred

0.019

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.097

gMVP

0.19

Mutation Taster

=98/2

polymorphism (auto)

(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