rs2274084

Positions:

chr13-20189503-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_004004.6(GJB2):c.79G>A(p.Val27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,144 control chromosomes in the GnomAD database, including 4,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 418 hom., cov: 32)

Exomes 𝑓: 0.018 ( 3603 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 6.12

Variant links:

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

GJB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a transmembrane_region Helical (size 19) in uniprot entity CXB2_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_004004.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0041432083).

BP6

Variant 13-20189503-C-T is Benign according to our data. Variant chr13-20189503-C-T is described in ClinVar as [Benign]. Clinvar id is 36279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189503-C-T is described in Lovd as [Likely_benign]. Variant chr13-20189503-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.79G>A	p.Val27Ile	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.79G>A	p.Val27Ile	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.79G>A	p.Val27Ile	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.79G>A	p.Val27Ile	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3943

AN:

152180

Hom.:

419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0540

AC:

13514

AN:

250230

Hom.:

1750

AF XY:

0.0444

AC XY:

6013

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.222

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.277

Gnomad SAS exome

AF:

0.00552

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.0331

GnomAD4 exome

AF:

0.0176

AC:

25688

AN:

1461846

Hom.:

3603

Cov.:

AF XY:

0.0164

AC XY:

11950

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.213

Gnomad4 ASJ exome

AF:

0.0168

Gnomad4 EAS exome

AF:

0.334

Gnomad4 SAS exome

AF:

0.00693

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000725

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0259

AC:

3949

AN:

152298

Hom.:

418

Cov.:

AF XY:

0.0308

AC XY:

2293

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00397

Gnomad4 AMR

AF:

0.137

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.282

Gnomad4 SAS

AF:

0.0135

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0164

Hom.:

686

Bravo

AF:

0.0393

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.0454

AC:

5509

Asia WGS

AF:

0.0980

AC:

342

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	Val27Ile in exon 2 of GJB2: This variant is benign based on its high frequency i n the general population (rs2274084) with a homozygous frequency of 12-20% in th e Asian population. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2015	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 1A

Benign:5

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2015	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal dominant nonsyndromic hearing loss 3A

Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Ichthyosis, hystrix-like, with hearing loss

Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 25, 2017

- -

Nonsyndromic genetic hearing loss

Benign:1

Benign, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 31, 2020

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.79G>A variant (p.Val27Ile) in GJB2 gene is 27,2% (5547/ 19950 East Asian alleles with 95% CI), 21,7% in Latino population and 4,97% in all ethnic groups from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering very strong evidence against pathogenicity for autosomal recessive hearing loss variants (BA1). The c.79G>A variant has been detected in high frequency in control individuals among different population (PMID: 10633133, 10983956, 15504600, 23503914, 24645897). This variant has been found in cis with pathogenic variants, applying to BP2 (PMID: 24158611). Besides, functional studies showed that p.Val27Ile mutant generated electrical conductance equal to wild type between paired Xenopus laevis oocytes. The same result was obtained when p.Val27Ile mutant was co-injected to hWtCX30, (PMID: 16300957; BS3_Supporting). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss BA1, BP2 and BS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

.;.;D

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-1.8

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

2.4e-9

P;P

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.66

N;N;.

REVEL

Uncertain

0.57

Sift

Benign

0.19

T;T;.

Sift4G

Benign

0.22

T;T;.

Polyphen

1.0

D;D;D

Vest4

0.15

MPC

0.060

ClinPred

0.053

GERP RS

5.2

Varity_R

0.59

gMVP

0.83

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