rs104894398

chr13-20189443-C-Achr13-20189443-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004004.6(GJB2):c.139G>T(p.Glu47Ter) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 7.85

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]

ACMG classification

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 197 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/exons	MANE	UniProt
GJB2	NM_004004.6	c.139G>T	p.Glu47Ter	stop_gained	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.139G>T	p.Glu47Ter	stop_gained	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.139G>T	p.Glu47Ter	stop_gained	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.139G>T	p.Glu47Ter	stop_gained	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152180 Hom.: 0 Cov.: 33

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: 32 AN: 250772 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135532

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.: 0 Cov.: 33 AF XY: 0.000113 AC XY: 82 AN XY: 726012

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: 17 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74354

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.: 0

Bravo AF: 0.000193

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 26, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	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 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2012	- -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 08, 2018	This variant was identified in compound heterozygosity with a second variant in GJB2 in a male patient with congenital bilateral moderate hearing loss. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 04, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 28, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -

Hearing impairment Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	Apr 12, 2021	PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Moderate, PM5_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jan 10, 2017

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 21, 2020

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). -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 31, 2021

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 27, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
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

Other links and lift over

dbSNP: rs104894398; hg19: chr13-20763582;