chr13-20189241-T-C

Position:

chr13-20189241-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000382848.5(GJB2):c.341A>G(p.Glu114Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,613,590 control chromosomes in the GnomAD database, including 688 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E114K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0069 ( 93 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 595 hom. )

Consequence

GJB2
ENST00000382848.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 0.431

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000382848.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0017281473).

BP6

Variant 13-20189241-T-C is Benign according to our data. Variant chr13-20189241-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189241-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.341A>G	p.Glu114Gly	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.341A>G	p.Glu114Gly	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.341A>G	p.Glu114Gly	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.341A>G	p.Glu114Gly	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.00696

AC:

1059

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.00952

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.0149

AC:

3740

AN:

250202

Hom.:

321

AF XY:

0.0139

AC XY:

1875

AN XY:

135322

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0137

Gnomad EAS exome

AF:

0.186

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.0000475

Gnomad NFE exome

AF:

0.000530

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00545

AC:

7957

AN:

1461292

Hom.:

595

Cov.:

AF XY:

0.00533

AC XY:

3875

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.167

Gnomad4 SAS exome

AF:

0.00381

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.000227

Gnomad4 OTH exome

AF:

0.00601

GnomAD4 genome

AF:

0.00693

AC:

1055

AN:

152298

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

618

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.178

Gnomad4 SAS

AF:

0.00953

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.0101

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0146

AC:

1768

Asia WGS

AF:

0.0490

AC:

170

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2014	Glu114Gly in exon 2 of GJB2: This variant is not expected to have clinical signi ficance because it has been identified in 10-20% Asian chromosomes by several st udies (http://www.1000genomes.org; dbSNP rs2274083; Park 2000, Choung 2002, Watt anasirichaigoon 2004, Tekin 2010, Tsukada 2010, Wei 2013). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 1A

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of autosomal recessive and autosomal dominant deafness. (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (15 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. This variant has been identified in cis with another variant; c.79G>A in greater than 15 unrelated families with hearing loss and in greater than 17 unaffected controls. This variant has been reported multiple times as a polymorphism (ClinVar, PMID: 31195736, PMID: 19366456, PMID 34161886). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 13, 2016	Variant summary: The c.341A>G (p.E114G) in GJB2 gene is a missense change that alters a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1.5%, predominantly in individuals of East Asian descent (18,8%) including numerous homozygous occurrences. This frequency suggests that the variant is a common ethnic-specific functional polymorphism. The variant has been reported to be mainly found in complex form (in cis with V27I) and in trans with V27I ( as well as with other variants) in both affected and unaffected individuals. Ogawa et al., (2014) report this complex variant to be found in unaffected individual who also carried p.Y136X on the other allele. In several patients reported by Dai et al, this variant occurred as complex forms p.[E114G;V27I] and [E114G;V27I;R127H] in compound heterozygosity swith known pathogenic variants, such as c.35delG, c.235delC, c.299_300delAT,Y125X, and c.424_426delTTC. Of typical observation, two patients were compound heterozygous for this variant and c.235delC. Furthermore, the complex p.[E114G;V27I] also co-occurred in cis with a known pathogenic variant (V37I) in four patients suggesting this complex is not pathogenic. Several independent groups showed that E114 in isolation or in complex with V27I formed gap junctions comparable to controls. In the field, this variant is widely accepted to be a polymorphism (Shearer et al., 2014). Taken together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 19, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nonsyndromic hearing loss 3A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ichthyosis, hystrix-like, with hearing loss

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.49

T;T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.79

.;.;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

2.0

M;M;M

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.080

N;N;.

REVEL

Benign

0.28

Sift

Benign

0.23

T;T;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.0010

B;B;B

Vest4

0.028

MPC

0.043

ClinPred

0.026

GERP RS

5.3

Varity_R

0.17

gMVP

0.87

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