rs2274084

chr13-20189503-C-T

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.79G>A(p.Val27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,144 control chromosomes in the GnomAD database, including 4,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (418 hom., cov: 32)
  • Exomes 𝑓: 0.018 (3603 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 6.12

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004004.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041432083).
• BP6: Variant 13-20189503-C-T is Benign according to our data. Variant chr13-20189503-C-T is described in ClinVar as [Benign]. Clinvar id is 36279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189503-C-T is described in Lovd as [Likely_benign]. Variant chr13-20189503-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.79G>A	p.Val27Ile	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.79G>A	p.Val27Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.79G>A	p.Val27Ile	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.79G>A	p.Val27Ile	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3943 AN: 152180 Hom.: 419 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0540 AC: 13514 AN: 250230 Hom.: 1750 AF XY: 0.0444 AC XY: 6013 AN XY: 135380

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.277

Gnomad SAS exome AF: 0.00552

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0176 AC: 25688 AN: 1461846 Hom.: 3603 Cov.: 33 AF XY: 0.0164 AC XY: 11950 AN XY: 727222

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.334

Gnomad4 SAS exome AF: 0.00693

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000725

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0259 AC: 3949 AN: 152298 Hom.: 418 Cov.: 32 AF XY: 0.0308 AC XY: 2293 AN XY: 74480

Gnomad4 AFR AF: 0.00397

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0164 Hom.: 686

Bravo AF: 0.0393

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.0454 AC: 5509

Asia WGS AF: 0.0980 AC: 342 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	Val27Ile in exon 2 of GJB2: This variant is benign based on its high frequency i n the general population (rs2274084) with a homozygous frequency of 12-20% in th e Asian population. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 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	GeneDx	Dec 30, 2015	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2015	- -
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	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

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 recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 25, 2017

- -

Nonsyndromic genetic hearing loss Benign:1

Benign, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 31, 2020

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.79G>A variant (p.Val27Ile) in GJB2 gene is 27,2% (5547/ 19950 East Asian alleles with 95% CI), 21,7% in Latino population and 4,97% in all ethnic groups from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering very strong evidence against pathogenicity for autosomal recessive hearing loss variants (BA1). The c.79G>A variant has been detected in high frequency in control individuals among different population (PMID: 10633133, 10983956, 15504600, 23503914, 24645897). This variant has been found in cis with pathogenic variants, applying to BP2 (PMID: 24158611). Besides, functional studies showed that p.Val27Ile mutant generated electrical conductance equal to wild type between paired Xenopus laevis oocytes. The same result was obtained when p.Val27Ile mutant was co-injected to hWtCX30, (PMID: 16300957; BS3_Supporting). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss BA1, BP2 and BS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.8	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	2.4e-9	P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.66	N;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.22	T;T;.
Polyphen		1.0	D;D;D
Vest4		0.15
MPC		0.060
ClinPred		0.053	T
GERP RS		5.2
Varity_R		0.59
gMVP		0.83

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: rs2274084; hg19: chr13-20763642; COSMIC: COSV67010703; COSMIC: COSV67010703;