rs8178046

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006904.7(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. 14/19 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
NM_006904.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.962

Publications

17 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=0.0030925572).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.2083C>T	p.Pro695Ser	missense_variant	Exon 19 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2 link	c.2083C>T	p.Pro695Ser	missense_variant	Exon 19 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PRKDC	ENST00000314191.7 link	c.2083C>T	p.Pro695Ser	missense_variant	Exon 19 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7 link	c.2083C>T	p.Pro695Ser	missense_variant	Exon 19 of 85	1		ENSP00000345182.4
PRKDC	ENST00000541488.1 link	n.22C>T		non_coding_transcript_exon_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.00980

AC:

1956

AN:

199624

AF XY:

0.00918

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 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

African (AFR)

AF:

0.00241

AC:

AN:

32808

American (AMR)

AF:

0.00515

AC:

206

AN:

39980

Ashkenazi Jewish (ASJ)

AF:

0.00903

AC:

230

AN:

25472

East Asian (EAS)

AF:

0.0000519

AC:

AN:

38556

South Asian (SAS)

AF:

0.000504

AC:

AN:

81322

European-Finnish (FIN)

AF:

0.00587

AC:

301

AN:

51282

Middle Eastern (MID)

AF:

0.00942

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0183

AC:

20033

AN:

1092630

Other (OTH)

AF:

0.00997

AC:

590

AN:

59162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

995

1990

2985

3980

4975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.0112

AC:

1713

AN:

152292

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

767

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41556

American (AMR)

AF:

0.00752

AC:

115

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00462

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0194

AC:

1323

AN:

68024

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

187

280

374

467

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:

0.0160

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

Sep 13, 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

0.082

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

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

PhyloP100

0.96

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

Mutation Taster

=99/1

polymorphism

(source)

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

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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