NM_004004.6:c.139G>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004004.6(GJB2):c.139G>T(p.Glu47*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GJB2
NM_004004.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26

Conservation

PhyloP100: 7.85

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 57 pathogenic variants in the truncated region.

PP5

Variant 13-20189443-C-A is Pathogenic according to our data. Variant chr13-20189443-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 17005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189443-C-A is described in Lovd as [Pathogenic]. Variant chr13-20189443-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.139G>T	p.Glu47*	stop_gained	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.139G>T	p.Glu47*	stop_gained	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.139G>T	p.Glu47*	stop_gained	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.139G>T	p.Glu47*	stop_gained	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000128

AC:

AN:

250772

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000121

AC:

176

AN:

1460126

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

726012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000112

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Mar 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 180 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9336442, 15070423, 32645618, 31589614, 29871260, 15964725, 30094485, 22429511, 29447821, 29625052, 30275481, 31160754, 33096615, 26553399, 21465647, 26990548, 27153395, 33105617) -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu47*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 180 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894398, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic hearing loss (PMID: 9336442, 15070423, 21465647, 22429511, 26553399). ClinVar contains an entry for this variant (Variation ID: 17005). For these reasons, this variant has been classified as Pathogenic. -

Aug 28, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB2 c.139G>T; p.Glu47Ter variant (rs104894398) is reported multiple times in the literature in individuals with nonsyndromic hearing loss who are homozygous for the variant or compound heterozygous with another pathogenic GJB2 variant (Ben Said 2012, Denoyelle 1997, Dodson 2011, Rabionet 2000, Roux 2004). This variant is reported in ClinVar (Variation ID: 17005) and is found in the general population with an overall allele frequency of 0.01% (35/282166 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Ben Said M et al. Segregation of a new mutation in SLC26A4 and p.E47X mutation in GJB2 within a consanguineous Tunisian family affected with Pendred syndrome. Int J Pediatr Otorhinolaryngol. 2012 Jun;76(6):832-6. PMID: 22429511 Denoyelle F et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997 Nov;6(12):2173-7. PMID: 9336442 Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. PMID: 21465647 Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4. PMID: 10982180 Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5. PMID: 15070423 -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 09, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. Occurs in three or more cases with a recessive pathogenic variant in the same gene. -

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:9

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PM3_VeryStrong+PP1_Strong -

Nov 08, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified in compound heterozygosity with a second variant in GJB2 in a male patient with congenital bilateral moderate hearing loss. -

May 09, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 06, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GJB2 c.139G>T (p.Glu47X) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.167delT, p.Leu56fsX26; c.169C>T, p.Gln57X; c.176_191delGCTGCAAGAACGTGTG, p.Gly59fsX18; c.235delC, p.Leu79fsX3). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 23/128870 control chromosomes at a frequency of 0.0001785, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant is a common variant found in NSHL patients (homozygotes and compound heterozygotes) (Denoyelle_HMG_1997, Snoeckx_AJHG_2005, Dai_J Trans Med_2009), including one patient where it occurred as a trimutation, p.S19R/p.R32S/p.E47* (Martinez-Saucedo_IJPO_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jun 02, 2023

Integrating Genomics into Medicine, Frazer Institute, University Of Queensland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_004004.5(GJB2):c.139G>T(E47*) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 21465647 and 17041943. Classification of NM_004004.5(GJB2):c.139G>T(E47*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -

Hearing impairment

Pathogenic:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Moderate, PM5_Moderate -

Hearing loss

Pathogenic:1

Jan 10, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Mar 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Aug 21, 2020

INGEBI, INGEBI / CONICET

Significance: Pathogenic

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 the c.139 G>T (p.Glu47*) variant in the GJB2 gene is 0.02% (13/35412) of Latino chromosomes by the Genome Aggregation Database http://gnomad.broadinstitute.org; (calculated by using inverse allele frequency at ttps://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting rule. The p.Glu47* variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID: 9336442, 10905664, 12910486, 14985372, 24158611). The c.139G>T variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: (PVS1, PM2_Supporting, PM3_VeryStrong). -

Rare genetic deafness

Pathogenic:1

Nov 27, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu47X variant has been reported in over 20 probands with hearing loss, many of whom were homozygous or compound heterozygous with another GJB2 variant (Kenna 2001, Kenna 2001, Abidi 2007, Denoyelle 1997, Ben Arab 2000, Chora 2010, Dalamón 2005, Marlin 2005, Masmoudi 2000, Neocleous 2006, Pallares-Ruiz 2002, Rabionet 2000, Ravecca 2005, Samanich 2007, Toth 2004, Wang 2009, Wu 2003). It has been identified in 0.03% (13/35412) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant leads to a premature stop codon at position 47, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong. -

GJB2-related disorder

Pathogenic:1

Sep 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GJB2 c.139G>T variant is predicted to result in premature protein termination (p.Glu47*). This variant has been reported to be causative for autosomal recessive sensorineural hearing loss (Denoyelle et al. 1997. PubMed ID: 9336442; Roux et al. 2004. PubMed ID: 15070423; Ben Said et al. 2012. PubMed ID: 22429511). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.97

Vest4

0.89

GERP RS

5.2

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