2-178461008-C-T

Position:

chr2-178461008-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001042702.5(PJVK):c.793C>T(p.Arg265Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,613,510 control chromosomes in the GnomAD database, including 4,575 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.054 ( 314 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4261 hom. )

Consequence

PJVK
NM_001042702.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

PJVK (HGNC:29502): (pejvakin) The protein encoded by this gene is a member of the gasdermin family, a family which is found only in vertebrates. The encoded protein is required for the proper function of auditory pathway neurons. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal recessive type 59 (DFNB59). [provided by RefSeq, Dec 2008]

PJVK links:

PJVK (HGNC:):

PJVK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028128922).

BP6

Variant 2-178461008-C-T is Benign according to our data. Variant chr2-178461008-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43871.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr2-178461008-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PJVK	NM_001042702.5 linkuse as main transcript	c.793C>T	p.Arg265Cys	missense_variant	7/7	ENST00000644580.2	NP_001036167.1	Q0ZLH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2 linkuse as main transcript	c.793C>T	p.Arg265Cys	missense_variant	7/7		NM_001042702.5	ENSP00000495855.2		Q0ZLH3

Frequencies

GnomAD3 genomes

AF:

0.0545

AC:

8290

AN:

152044

Hom.:

314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0525

Gnomad ASJ

AF:

0.0522

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0745

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0833

Gnomad OTH

AF:

0.0507

GnomAD3 exomes

AF:

0.0561

AC:

13990

AN:

249418

Hom.:

513

AF XY:

0.0562

AC XY:

7605

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.0540

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.0734

Gnomad NFE exome

AF:

0.0816

Gnomad OTH exome

AF:

0.0634

GnomAD4 exome

AF:

0.0713

AC:

104255

AN:

1461348

Hom.:

4261

Cov.:

AF XY:

0.0703

AC XY:

51081

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.0417

Gnomad4 ASJ exome

AF:

0.0512

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0233

Gnomad4 FIN exome

AF:

0.0739

Gnomad4 NFE exome

AF:

0.0815

Gnomad4 OTH exome

AF:

0.0631

GnomAD4 genome

AF:

0.0545

AC:

8286

AN:

152162

Hom.:

314

Cov.:

AF XY:

0.0534

AC XY:

3969

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0143

Gnomad4 AMR

AF:

0.0524

Gnomad4 ASJ

AF:

0.0522

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0205

Gnomad4 FIN

AF:

0.0745

Gnomad4 NFE

AF:

0.0833

Gnomad4 OTH

AF:

0.0501

Alfa

AF:

0.0714

Hom.:

382

TwinsUK

AF:

0.0785

AC:

291

ALSPAC

AF:

0.0654

AC:

252

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0837

AC:

687

ExAC

AF:

0.0580

AC:

7001

EpiCase

AF:

0.0829

EpiControl

AF:

0.0779

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 26, 2011	The Arg265Cys variant in DFNB59 is not expected to have clinical significance du e to its equal occurrence in probands and controls (Hashemzadeh-Chaleshtori 2007 , dbSNP-rs17304212). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 59

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

.;T;.;T;.;.;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;.;.;.;.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

.;N;.;N;.;.;.;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.67

.;.;.;N;.;.;.;N

REVEL

Benign

0.23

Sift

Uncertain

0.0050

.;.;.;D;.;.;.;D

Sift4G

Uncertain

0.052

.;.;.;T;.;.;.;T

Polyphen

0.99

.;D;.;D;.;.;.;D

Vest4

0.22, 0.10

MPC

0.50

ClinPred

0.015

GERP RS

6.0

Varity_R

0.11

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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