13-20188965-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_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

Publications

46 publications found

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 Gene-Disease associations (from GenCC):

Bart-Pumphrey syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
ichthyosis, hystrix-like, with hearing loss
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
keratoderma hereditarium mutilans
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
palmoplantar keratoderma-deafness syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
autosomal recessive nonsyndromic hearing loss 1A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal dominant keratitis-ichthyosis-hearing loss syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
autosomal dominant nonsyndromic hearing loss 3A
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
KID syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJB2 links:

ENSG00000296095 (HGNC:):

ENSG00000296095 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_004004.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 111 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: -0.72044 (below the threshold of 3.09). Trascript score misZ: 0.4379 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 1A, ichthyosis, hystrix-like, with hearing loss, keratoderma hereditarium mutilans, hearing loss, autosomal recessive, Bart-Pumphrey syndrome, palmoplantar keratoderma-deafness syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss, KID syndrome.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 44763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.617A>G	p.Asn206Ser	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 link	c.617A>G	p.Asn206Ser	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GJB2	ENST00000382848.5 link	c.617A>G	p.Asn206Ser	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2 link	c.617A>G	p.Asn206Ser	missense_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1 link	n.232-3385A>G		intron_variant	Intron 1 of 3

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

GnomAD2 exomes

AF:

0.0000956

AC:

AN:

251052

AF XY:

0.0000663

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000537

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

1111984

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41578

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000683

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

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 11, 2021

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 21, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

May 11, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:4

Jan 03, 2020

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 10, 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.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. -

Sep 16, 2020

Natera, Inc.

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

May 22, 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 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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rare genetic deafness

Pathogenic:1

Aug 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

GJB2-related disorder

Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

6.2

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

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over