rs7830743

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.10301T>C(p.Ile3434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,593,232 control chromosomes in the GnomAD database, including 8,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2189 hom., cov: 32)

Exomes 𝑓: 0.072 ( 6716 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.231

Publications

38 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=0.0017988086).

BP6

Variant 8-47798394-A-G is Benign according to our data. Variant chr8-47798394-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 379415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.10301T>C	p.Ile3434Thr	missense_variant	Exon 73 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.10301T>C	p.Ile3434Thr	missense_variant	Exon 73 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRKDC	ENST00000314191.7 link	c.10301T>C	p.Ile3434Thr	missense_variant	Exon 73 of 86	1	NM_006904.7	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7 link	c.10301T>C	p.Ile3434Thr	missense_variant	Exon 73 of 85	1		ENSP00000345182.4	P78527-2
PRKDC	ENST00000697603.1 link	c.2978T>C	p.Ile993Thr	missense_variant	Exon 20 of 33			ENSP00000513358.1	A0A8V8TMR1
PRKDC	ENST00000697602.1 link	n.874T>C		non_coding_transcript_exon_variant	Exon 5 of 18

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20257

AN:

152122

Hom.:

2188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.272

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.213

Gnomad ASJ

AF:

0.0910

Gnomad EAS

AF:

0.0838

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0496

Gnomad OTH

AF:

0.135

GnomAD2 exomes

AF:

0.119

AC:

27068

AN:

226646

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.281

Gnomad AMR exome

AF:

0.325

Gnomad ASJ exome

AF:

0.0935

Gnomad EAS exome

AF:

0.0689

Gnomad FIN exome

AF:

0.0388

Gnomad NFE exome

AF:

0.0542

Gnomad OTH exome

AF:

0.0990

GnomAD4 exome

AF:

0.0716

AC:

103208

AN:

1440992

Hom.:

6716

Cov.:

AF XY:

0.0728

AC XY:

52116

AN XY:

715512

show subpopulations

African (AFR)

AF:

0.289

AC:

9376

AN:

32462

American (AMR)

AF:

0.306

AC:

12287

AN:

40150

Ashkenazi Jewish (ASJ)

AF:

0.0923

AC:

2309

AN:

25012

East Asian (EAS)

AF:

0.0884

AC:

3498

AN:

39566

South Asian (SAS)

AF:

0.156

AC:

12849

AN:

82412

European-Finnish (FIN)

AF:

0.0387

AC:

2046

AN:

52850

Middle Eastern (MID)

AF:

0.0961

AC:

543

AN:

5652

European-Non Finnish (NFE)

AF:

0.0500

AC:

55174

AN:

1103376

Other (OTH)

AF:

0.0861

AC:

5126

AN:

59512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4249

8498

12746

16995

21244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.133

AC:

20284

AN:

152240

Hom.:

2189

Cov.:

AF XY:

0.133

AC XY:

9914

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.272

AC:

11279

AN:

41516

American (AMR)

AF:

0.213

AC:

3254

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

316

AN:

3472

East Asian (EAS)

AF:

0.0840

AC:

435

AN:

5180

South Asian (SAS)

AF:

0.164

AC:

790

AN:

4828

European-Finnish (FIN)

AF:

0.0322

AC:

342

AN:

10610

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0496

AC:

3376

AN:

68030

Other (OTH)

AF:

0.137

AC:

289

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

827

1654

2480

3307

4134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0854

Hom.:

1979

Bravo

AF:

0.158

TwinsUK

AF:

0.0520

AC:

193

ALSPAC

AF:

0.0496

AC:

191

ESP6500AA

AF:

0.261

AC:

975

ESP6500EA

AF:

0.0568

AC:

467

ExAC

AF:

0.115

AC:

13833

Asia WGS

AF:

0.144

AC:

501

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -

Jan 05, 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: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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.042

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.40

N;N

PhyloP100

-0.23

PrimateAI

Benign

0.27

REVEL

Benign

0.075

Sift4G

Benign

0.50

T;T

Polyphen

0.0

B;.

Vest4

0.0070

MPC

0.21

ClinPred

0.0021

GERP RS

-7.7

Varity_R

0.039

gMVP

0.048

Mutation Taster

=96/4

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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rs7830743

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