rs371024165

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The ENST00000382848.5(GJB2):c.94C>T(p.Arg32Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.94

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.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000382848.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189487-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 44766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 13-20189488-G-A is Pathogenic according to our data. Variant chr13-20189488-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 188758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189488-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.94C>T	p.Arg32Cys	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.94C>T	p.Arg32Cys	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.94C>T	p.Arg32Cys	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.94C>T	p.Arg32Cys	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250496

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135480

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000145

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000531

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000635

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27153395, 27045574, 19366456, 25087612, 25388846, 12865758, 16380907, 25270357, 14985372, 20381175, 27067584, 26540915, 22925408, 20083784, 19235794, 19157576, 17666888, 15967879, 12885339, 21465647, 31163360, 22695344, 15146474, 26346709, 19390476, 15365987, 11102979, 19371219, 30275481, 34426522, 36048236) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 32 of the GJB2 protein (p.Arg32Cys). This variant is present in population databases (rs371024165, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 11102979, 19371219, 21465647, 26346709, 27045574). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188758). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19157576, 20154630, 22925408). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 21, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2017	Variant summary: The GJB2 c.94C>T (p.Arg32Cys) variant causes a missense change involving the alteration of a conserved nucleotide located in the Connexin, N-terminal domain (IPR013092) (InterPro). 5/5 in silico tools predict damaging outcome for this variant. The variant was found in the control population dataset of ExAC and publications in 5/122742 control chromosomes at a frequency of 0.0000407, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant was reported in several patients with NSHL in homozygous state and compound heterozygous state with other pathogenic variants, including evidence of cosegregation with disease (Prasad_2000, Pandya_2003, Toth_2004, Snoeckx_2005, Dai_2009, Shan_2010, Dodson_2011, Bazazzadegan_2012, Rayess_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Another missense change at the same residue p.Arg32His has also been classified as pathogenic by multiple submitters in ClinVar. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 18, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 28, 2018

The GJB2 (Connexin 26) c.94C>T; p.Arg32Cys variant (rs371024165) has been previously identified in patients with a suspicion of GJB2-realted deafness, either as a homozygote (Moctar 2016), or as part of a trans-heterozygous (bi-allelic) combination with another pathogenic variant (Prasad 2000, Xia 2016, Moctar 2016). It has also been identified as a rare variant in several large-scale sequencing studies of affected populations (selected references: Snoeckx 2005, Dodson 2011, de la Luz Arenas-Sordo 2012, Bazazzadegan 2012). Consistent with a recessive carrier frequency, this variant is found in the general population with an allele frequency in African populations of 0.04% (10/24,020 alleles) in the Genome Aggregation Database. The arginine residue at this position is highly conserved across multiple species (Alamut Software v 2.11), and computational programs (SIFT, PolyPhen2) predict this variant to be damaging to protein function. Additionally, as listed in the HGMD database (Stenson 2017) other amino acid substitutions at this codon have been implicated in hearing loss (Gly, His, Leu, Ser). Taken together, we consider the c.94C>T; p.Arg32Cys variant to be pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2024

The p.Arg32Cys variant in GJB2 has been reported in at least 13 individuals with hearing loss, including 3 homozygotes and 8 compound heterozygotes, and segregated with hearing loss in two affected relatives from 2 families (Prasad 2000 PMID: 11102979, Cryns 2004 PMID: 14985372, Primignani 2009 PMID: 19371219, Dai 2009 PMID: 19366456, Shan 2010 PMID: 20381175, Dodson 2011 PMID: 21465647, Bazazzadegan 2012 PMID: 22695344, Xia 2016 PMID: 27045574, Moctar 2016 PMID: 27067584, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 188758). It has been identified in 0.036% (27/74926) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0); however, its frequency is low enough to be consistent with the carrier frequency for autosomal recessive hearing loss. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg32His) has been identified in individuals with hearing loss and is classified as pathogenic by this laboratory. In summary, the p.Arg32Cys variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Moderate, PM5, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.7

H;H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.8

D;D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0090

D;D;.

Sift4G

Uncertain

0.015

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.95

MVP

0.98

MPC

0.32

ClinPred

0.99

GERP RS

5.2

Varity_R

0.79

gMVP

0.99

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