13-20189125-C-T

Variant names:

Variant summary

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

The NM_004004.6(GJB2):c.457G>A(p.Val153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,614,130 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 198 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:21

Conservation

PhyloP100: 0.240

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 chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) in NM_004004.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0035775304).

BP6

Variant 13-20189125-C-T is Benign according to our data. Variant chr13-20189125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189125-C-T is described in Lovd as [Benign]. Variant chr13-20189125-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.457G>A	p.Val153Ile	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.457G>A	p.Val153Ile	missense_variant	Exon 2 of 2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.457G>A	p.Val153Ile	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.457G>A	p.Val153Ile	missense_variant	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

623

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0537

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00925

AC:

2324

AN:

251112

Hom.:

AF XY:

0.0117

AC XY:

1590

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0536

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.00364

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00561

AC:

8203

AN:

1461794

Hom.:

198

Cov.:

AF XY:

0.00733

AC XY:

5333

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0532

Gnomad4 FIN exome

AF:

0.00236

Gnomad4 NFE exome

AF:

0.00234

Gnomad4 OTH exome

AF:

0.00649

GnomAD4 genome

AF:

0.00409

AC:

623

AN:

152336

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

365

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0537

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00392

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00392

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.0105

AC:

1279

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val153Ile in exon 2 of GJB2: This variant has been reported in the literature as both a benign polymorphism (Connexins and Deafness Website and other reports) as well as a pathogenic variant (Snoeckx 2005 and other reports). Several repor ts show that this variant occurs at an equal frequency in both hearing loss prob ands and the general population (Guerci 2007, Abidi 2008, RamShankar 2003, Roux 2004, Rickard 2001). It was also identified in 5.6% (922/16488) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs111033186), including 31 homozygous individuals. Functional studie s have demonstrated no impact to synthesis and localization of the connexin 26 p rotein (Guerci 2007). It has also been reported in a homozygous state in 3 indiv iduals with normal hearing (Guerci 2007, RamShankar 2003) as well as identified as a compound heterozygote in a normal hearing individual with the p.Met34Thr mu tation (Malikova 2004). And finally, this variant did not segregate with hearing loss in two kindreds (Gasmelseed 2004, Malikova 2004). In summary, these data s uggest that the p.Val153Ile variant is benign. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 1A

Benign:4

Jul 01, 2021

Pars Genome Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 14, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 3A

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, autosomal recessive

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Ichthyosis, hystrix-like, with hearing loss

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nonsyndromic genetic hearing loss

Benign:1

Aug 31, 2020

INGEBI, INGEBI / CONICET

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.457G>A p.Val153Ile in GJB2 gene is 5% (1642/30610 Southeast Asian chromosomes with 95% CI) 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). Functional studies demonstrated that mutants lost their abilities to form functional gap junction channels (PMID: 15241677). However, it was shown that there were not differences between p.Val153Ile mutant and wild-type results in dye transfer assay (Guerci V.I, et al 2007). Therefore, functional data was not counted. Besides, the p.Val153Ile change was detected in trans with c.35delG and in homozygous state in normal-hearing individuals applying to BS2 rule (PMID:11493200, 12746422). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss (BA1 and BS2). -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Benign:1

May 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Uncertain

0.51

D;D;D

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.78

.;.;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

-0.30

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.21

N;N;.

REVEL

Uncertain

0.38

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0030

B;B;B

Vest4

0.037

MPC

0.034

ClinPred

0.0017

GERP RS

5.5

Varity_R

0.12

gMVP

0.80

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