rs79399438

Positions:

chr2-178461089-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042702.5(PJVK):c.874G>A(p.Gly292Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0261 in 1,613,996 control chromosomes in the GnomAD database, including 897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 86 hom., cov: 32)

Exomes 𝑓: 0.026 ( 811 hom. )

Consequence

PJVK
NM_001042702.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017353296).

BP6

Variant 2-178461089-G-A is Benign according to our data. Variant chr2-178461089-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178461089-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 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.874G>A	p.Gly292Arg	missense_variant	7/7	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2 linkuse as main transcript	c.874G>A	p.Gly292Arg	missense_variant	7/7		NM_001042702.5	ENSP00000495855	P1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4127

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0294

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.132

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0238

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0283

AC:

7062

AN:

249520

Hom.:

208

AF XY:

0.0271

AC XY:

3662

AN XY:

135368

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.136

Gnomad SAS exome

AF:

0.00703

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0232

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0259

AC:

37934

AN:

1461824

Hom.:

811

Cov.:

AF XY:

0.0254

AC XY:

18483

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0263

Gnomad4 AMR exome

AF:

0.0207

Gnomad4 ASJ exome

AF:

0.0206

Gnomad4 EAS exome

AF:

0.142

Gnomad4 SAS exome

AF:

0.00761

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.0241

Gnomad4 OTH exome

AF:

0.0299

GnomAD4 genome

AF:

0.0271

AC:

4130

AN:

152172

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1958

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0293

Gnomad4 AMR

AF:

0.0196

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.133

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.0238

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0270

Hom.:

157

Bravo

AF:

0.0284

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.0293

AC:

109

ESP6500EA

AF:

0.0218

AC:

179

ExAC

AF:

0.0288

AC:

3475

Asia WGS

AF:

0.0660

AC:

230

AN:

3478

EpiCase

AF:

0.0204

EpiControl

AF:

0.0229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly292Arg in Exon 07 of DFNB59: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (87/3024) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79399438). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 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. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -

Autosomal recessive nonsyndromic hearing loss 59

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.81

.;L;.;L;.;.;.;L

MutationTaster

Benign

0.0046

P;P

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.17

Sift

Uncertain

0.0070

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

Sift4G

Benign

0.12

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

Polyphen

0.88

.;P;.;P;.;.;.;P

Vest4

0.23, 0.15

MutPred

0.85

.;Loss of sheet (P = 0.0228);.;Loss of sheet (P = 0.0228);.;.;.;Loss of sheet (P = 0.0228);

MPC

0.23

ClinPred

0.015

GERP RS

5.9

Varity_R

0.18

gMVP

0.56

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