dbSNP rs56123237: PRKDC:p.Tyr4046Tyr (chr8-47776888-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_006904.7(PRKDC):c.12138C>T(p.Tyr4046Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,806 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

PRKDC
NM_006904.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.306

Publications

3 publications found

Variant links:

COSMIC-nc: COSV104628472

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 8-47776888-G-A is Benign according to our data. Variant chr8-47776888-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.306 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.12138C>T	p.Tyr4046Tyr	synonymous_variant	Exon 85 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.12045C>T	p.Tyr4015Tyr	synonymous_variant	Exon 84 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.12138C>T	p.Tyr4046Tyr	synonymous_variant	Exon 85 of 86	1	NM_006904.7	ENSP00000313420.3		P78527-1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00112

AC:

278

AN:

249100

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.00472

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00134

AC:

1962

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

959

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00478

AC:

160

AN:

33476

American (AMR)

AF:

0.000514

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.000846

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00135

AC:

1504

AN:

1111828

Other (OTH)

AF:

0.00244

AC:

147

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

107

215

322

430

537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00188

AC:

286

AN:

152196

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00402

AC:

167

AN:

41514

American (AMR)

AF:

0.000392

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00151

AC:

103

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00157

Hom.:

Bravo

AF:

0.00215

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRKDC: BP4, BP7 -

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

-0.57

CADD

Benign

0.60

(source)

DANN

Benign

0.48

PhyloP100

0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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