8-47817561-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_006904.7(PRKDC):c.9446G>A(p.Gly3149Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,576,712 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 55 hom. )

Consequence

PRKDC
NM_006904.7 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.35

Publications

7 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 -16 ACMG points.

BP6

Variant 8-47817561-C-T is Benign according to our data. Variant chr8-47817561-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00387 (589/152154) while in subpopulation SAS AF = 0.0251 (121/4820). AF 95% confidence interval is 0.0215. There are 4 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	Exon 68 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	Exon 68 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRKDC	ENST00000314191.7 link	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	Exon 68 of 86	1	NM_006904.7	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7 link	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	Exon 68 of 85	1		ENSP00000345182.4	P78527-2
PRKDC	ENST00000697603.1 link	c.2123G>A	p.Gly708Asp	missense_variant, splice_region_variant	Exon 15 of 33			ENSP00000513358.1	A0A8V8TMR1
PRKDC	ENST00000697607.1 link	n.978G>A		non_coding_transcript_exon_variant	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00385

AC:

586

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00440

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00290

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00519

AC:

1114

AN:

214792

AF XY:

0.00625

show subpopulations

Gnomad AFR exome

AF:

0.00450

Gnomad AMR exome

AF:

0.00297

Gnomad ASJ exome

AF:

0.00573

Gnomad EAS exome

AF:

0.0000629

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00308

Gnomad OTH exome

AF:

0.00785

GnomAD4 exome

AF:

0.00374

AC:

5329

AN:

1424558

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

3078

AN XY:

707490

show subpopulations

African (AFR)

AF:

0.00434

AC:

143

AN:

32912

American (AMR)

AF:

0.00300

AC:

123

AN:

41046

Ashkenazi Jewish (ASJ)

AF:

0.00590

AC:

151

AN:

25604

East Asian (EAS)

AF:

0.000102

AC:

AN:

39336

South Asian (SAS)

AF:

0.0248

AC:

2049

AN:

82688

European-Finnish (FIN)

AF:

0.0000573

AC:

AN:

52368

Middle Eastern (MID)

AF:

0.0210

AC:

120

AN:

5712

European-Non Finnish (NFE)

AF:

0.00223

AC:

2422

AN:

1085734

Other (OTH)

AF:

0.00531

AC:

314

AN:

59158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

218

436

655

873

1091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00387

AC:

589

AN:

152154

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00441

AC:

183

AN:

41520

American (AMR)

AF:

0.00262

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0251

AC:

121

AN:

4820

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00290

AC:

197

AN:

67996

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00310

Hom.:

Bravo

AF:

0.00348

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00467

AC:

ESP6500EA

AF:

0.00306

AC:

ExAC

AF:

0.00486

AC:

585

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 01, 2017

GeneDx

Significance:Likely 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:Likely 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

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.077

T;.

Eigen

Benign

-0.084

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.8

L;L

PhyloP100

2.4

PrimateAI

Benign

0.48

REVEL

Benign

0.14

Sift4G

Benign

0.18

T;T

Polyphen

0.029

B;.

Vest4

0.17

MVP

0.47

MPC

0.26

ClinPred

0.012

GERP RS

5.7

Varity_R

0.28

gMVP

0.34

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -18

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