rs2274083

chr13-20189241-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_004004.6(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. 12/19 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 NM_004004.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.431

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 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 NM_004004.6
• 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	UniProt
GJB2	NM_004004.6	c.341A>G	p.Glu114Gly	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.341A>G	p.Glu114Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.341A>G	p.Glu114Gly	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.341A>G	p.Glu114Gly	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152180 Hom.: 95 Cov.: 33

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

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.: 33 AF XY: 0.00533 AC XY: 3875 AN XY: 726944

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.: 93 Cov.: 33 AF XY: 0.00830 AC XY: 618 AN XY: 74480

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.: 12

Bravo AF: 0.0101

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

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:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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:4

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	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	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	clinical testing	Athena Diagnostics	Nov 29, 2017	- -

Autosomal dominant nonsyndromic hearing loss 3A Benign:2

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	Pars Genome Lab	Jul 01, 2021	- -

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	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	21
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	D
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs2274083; hg19: chr13-20763380; COSMIC: COSV67010838;