rs199524714

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006904.7(PRKDC):c.4375C>T(p.His1459Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000574 in 1,581,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.11

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053417176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.4375C>T	p.His1459Tyr	missense_variant	Exon 34 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.4375C>T	p.His1459Tyr	missense_variant	Exon 34 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.4375C>T	p.His1459Tyr	missense_variant	Exon 34 of 86	1	NM_006904.7	ENSP00000313420.3		P78527-1
PRKDC	ENST00000338368.7 link	c.4375C>T	p.His1459Tyr	missense_variant	Exon 34 of 85	1		ENSP00000345182.4		P78527-2

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000292

AC:

AN:

202218

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

108328

show subpopulations

Gnomad AFR exome

AF:

0.000254

Gnomad AMR exome

AF:

0.000342

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.000588

AC:

840

AN:

1429244

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

417

AN XY:

707882

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.000527

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000719

Gnomad4 OTH exome

AF:

0.000455

GnomAD4 genome

AF:

0.000446

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000594

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000482

AC:

ExAC

AF:

0.000315

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRKDC: PM2, BP4 -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1459 of the PRKDC protein (p.His1459Tyr). This variant is present in population databases (rs199524714, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 475226). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRKDC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

PRKDC-related disorder

Uncertain:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PRKDC c.4375C>T variant is predicted to result in the amino acid substitution p.His1459Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.052% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.049

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.0015

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.49

REVEL

Benign

0.20

Sift4G

Benign

0.18

T;T

Polyphen

0.0090

B;.

Vest4

0.30

MVP

0.80

MPC

0.21

ClinPred

0.042

GERP RS

5.4

Varity_R

0.24

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over