rs111033294

Positions:

chr13-20188965-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_004004.6(GJB2):c.617A>G(p.Asn206Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000836 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 6.21

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 12 ACMG points.

PM1

In a helix (size 31) in uniprot entity CXB2_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_004004.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

PP5

Variant 13-20188965-T-C is Pathogenic according to our data. Variant chr13-20188965-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20188965-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.617A>G	p.Asn206Ser	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.617A>G	p.Asn206Ser	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.617A>G	p.Asn206Ser	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.617A>G	p.Asn206Ser	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.0000956

AC:

AN:

251052

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461708

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000184

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.0000810

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 206 of the GJB2 protein (p.Asn206Ser). This variant is present in population databases (rs111033294, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 12172394, 14985372, 15070423, 15967879). 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: 44763). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 15241677, 18684989, 23967136). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 08, 2021	The GJB2 c.617A>G; p.Asn206Ser variant (rs111033294) is reported in the literature in individuals with sensorineural hearing loss, either in the homozygous state (Marlin 2005) or in trans to other pathogenic GJB2 variants (Kenna 2001, Marlin 2001, Marlin 2005, Putcha 2007). This variant is found in the general population with an overall allele frequency of 0.01% (29/282456 alleles) in the Genome Aggregation Database and is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 44763). In functional assays, the p.Asn206Ser variant protein appears to be localized normally (Mese 2004, Fleishman 2006, Ambrosi 2013) and can form functional channels capable of electrical coupling, but these channels are less permeable to larger cations and exhibit reduced conductance compared to wildtype protein (Mese 2004, Mese 2008). Based on available information, this variant is considered to be pathogenic. References: Fleishman et al. The structural context of disease-causing mutations in gap junctions. J Biol Chem. 2006; 281(39): 28958-28963. Kenna et al. Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2001; 127(9): 1037-1042. Marlin et al. Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. Arch Otolaryngol Head Neck Surg. 2001; 127(8): 927-933. Marlin et al. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg. 2005; 131(6): 481-487. Mese et al. Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum Genet. 2004; 115(3): 191-199. Mese et al. Connexin26 deafness associated mutations show altered permeability to large cationic molecules. Am J Physiol Cell Physiol. 2008; 295(4): C966-974. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007; 9(7): 413-426. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Experimental evidence regarding the effect of this variant on protein function is conflicting. Although studies show reduced channel permeability to large cationic molecules, they also show it is similar to wildtype (PMID: 18684989, 15241677, 16864573, 23967136). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	Published in vitro studies demonstrate a damaging effect on the protein's function, with significantly reduced passage of dye and current through gap junction channels and slightly unstable hemichannels (Mese et al., 2008; Ambrosi et al., 2013); 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: 25262649, 26990548, 25087612, 15241677, 11493200, 25388846, 18988928, 17666888, 16864573, 15967879, 15070423, 14985372, 12865758, 12172394, 23891399, 23668481, 22796187, 24158611, 11556849, 16380907, 31370293, 31980526, 31160754, 34426522, 31589614, 33297549, 33096615, 36147510, 18684989, 23967136, 34032567) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 11, 2019	- -

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	Mar 10, 2017	Variant summary: The GJB2 c.617A>G (p.Asn206Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 10/119604 control chromosomes at a frequency of 0.0000836, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed the variant to result in channel malfunction with normal trafficking (Ambros_PNAS_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2020	NM_004004.5(GJB2):c.617A>G(N206S) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID: 15070423, 14985372, 15967879, 12172394 and 11493200. Classification of NM_004004.5(GJB2):c.617A>G(N206S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.617A>G;p.(Asn206Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 44763; PMID: 23668481; 16380907; 17666888; 15967879; 12172394) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 18684989, 15241677, 16864573, 23967136) - PS3_moderate. The variant is present at low allele frequencies population databases (rs111033294– gnomAD 0.001840%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asn206Ser) was detected in trans with a pathogenic variant (PMID: 23668481; 16380907; 17666888; 15967879; 12172394) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

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 c.617A>G, p.Asn206Ser is 0,031% in Latino chromosomes from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria meeting PM2_supp. This variant has been reported several times (more than 5) in trans with pathogenic variants individuals and also in homozygous state in hearing loss individuals (PMID: 23668481, 16380907, 17666888, 15967879, 12172394, 115556849, 15070423, 14985372, 11493200, 24158611; PM3_VeryStrong). p.Asn206Ser change in trans with a pathogenic variant segregated in one affected and unaffected siblings (Laboratory of Physiology and Genetics of Hearing, INGEBI internal data) meeting PP1_Moderate criteria. Computational data predicted a negative impact of the mutation to the protein (REVELscore: 0.775) applying to PP3 rule. Functional studies in Xenopus laevis oocytes and HeLa cells demonstrated a highly reduced function of mutant compared to WTCX26: decreased dye transfer, permeability to cationic and large molecules and conductance levels applying PS3_Moderate rule(PMID: 23967136, 18684989). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Sup, PP3, PP1_Mod , PM3_VeryStrong and PS3_Moderate. -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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

Mar 23, 2022

- -

GJB2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

The GJB2 c.617A>G variant is predicted to result in the amino acid substitution p.Asn206Ser. This variant has been reported as pathogenic for autosomal recessive non-syndromic hearing loss (Marlin et al 2001. PubMed ID: 11493200; Wu et al. 2002. PubMed ID: 12172394; Roux et al. 2004. PubMed ID: 15070423; Snoeckx et al. 2005. PubMed ID: 16380907; Putcha et al. 2007. PubMed ID: 17666888). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2017

The p.Asn206Ser variant in GJB2 has been reported in many individuals with heari ng loss (Kenna 2001, Wu 2002, Pandya 2003, Cryns 2004, Roux 2004, Snoeckx 2005, Marlin 2005, Putcha 2007, Rodriguez-Paris 2008, LMM data). At least 5 of these i ndividuals were homozygous or compound heterozygous with a second pathogenic var iant, and the variant segregated with hearing loss in at least 1 affected siblin g. This variant has also been identified in 0.05% (17/34414) of Latino chromosom es and 0.01% (9/126442) of European chromosomes by gnomAD (http://gnomad.broadin stitute.org); however, its frequency is low enough to be consistent with a reces sive carrier frequency. Computational prediction tools and conservation analysis are consistent with pathogenicity. Furthermore, in vitro functional studies sup port an impact on protein function (Mese 2004, Fleishman 2006, Mese 2008). In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss. ACMG/AMP Criteria applied: PM 3_VeryStrong, PM2_Supporting, PP3, PS3_Supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

.;.;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.0

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

D;D;.

REVEL

Pathogenic

0.78

Sift

Benign

0.067

T;T;.

Sift4G

Benign

0.18

T;T;.

Polyphen

1.0

D;D;D

Vest4

0.92

MVP

0.96

MPC

0.26

ClinPred

0.90

GERP RS

4.5

Varity_R

0.56

gMVP

0.92

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