8-47893227-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006904.7(PRKDC):c.3759G>A(p.Thr1253Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,612,656 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts 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. T1253T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 116 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 111 hom. )

Consequence

PRKDC
NM_006904.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.424

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 8-47893227-C-T is Benign according to our data. Variant chr8-47893227-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.424 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.3759G>A	p.Thr1253Thr	synonymous_variant	Exon 31 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2 link	c.3759G>A	p.Thr1253Thr	synonymous_variant	Exon 31 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 link	c.3759G>A	p.Thr1253Thr	synonymous_variant	Exon 31 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7 link	c.3759G>A	p.Thr1253Thr	synonymous_variant	Exon 31 of 85	1		ENSP00000345182.4

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3456

AN:

152154

Hom.:

116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0786

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00556

AC:

1316

AN:

236788

AF XY:

0.00415

show subpopulations

Gnomad AFR exome

AF:

0.0800

Gnomad AMR exome

AF:

0.00375

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000181

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000305

Gnomad OTH exome

AF:

0.00299

GnomAD4 exome

AF:

0.00233

AC:

3398

AN:

1460386

Hom.:

111

Cov.:

AF XY:

0.00202

AC XY:

1464

AN XY:

726378

show subpopulations

African (AFR)

AF:

0.0787

AC:

2633

AN:

33438

American (AMR)

AF:

0.00397

AC:

177

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39650

South Asian (SAS)

AF:

0.000163

AC:

AN:

86008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000240

AC:

267

AN:

1111266

Other (OTH)

AF:

0.00481

AC:

290

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0227

AC:

3461

AN:

152270

Hom.:

116

Cov.:

AF XY:

0.0213

AC XY:

1587

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0785

AC:

3261

AN:

41542

American (AMR)

AF:

0.00876

AC:

134

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68018

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

172

345

517

690

862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00783

Hom.:

Bravo

AF:

0.0257

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 06, 2016

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

Jan 30, 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

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.7

(source)

DANN

Benign

0.65

PhyloP100

-0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

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