Variant rs771482106 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006904.7(PRKDC):c.2245G>T(p.Val749Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V749A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.906

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.2245G>T	p.Val749Phe	missense_variant	20/86	ENST00000314191.7
PRKDC	NM_001081640.2 linkuse as main transcript	c.2245G>T	p.Val749Phe	missense_variant	20/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.2245G>T	p.Val749Phe	missense_variant	20/86	1	NM_006904.7	P1	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.2245G>T	p.Val749Phe	missense_variant	20/85	1			P78527-2
PRKDC	ENST00000541488.1 linkuse as main transcript	n.184G>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699950

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2024

The p.V749F variant (also known as c.2245G>T), located in coding exon 20 of the PRKDC gene, results from a G to T substitution at nucleotide position 2245. The valine at codon 749 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Benign

0.91

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.20

Sift

Benign

0.049

D;T

Sift4G

Benign

0.11

T;T

Polyphen

0.15

B;B

Vest4

0.83

MutPred

0.33

Gain of catalytic residue at V749 (P = 0.2218);Gain of catalytic residue at V749 (P = 0.2218);

MVP

0.64

MPC

0.46

ClinPred

0.69

GERP RS

0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.084

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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