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rs2274083

Variant summary

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

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

Scores

3
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

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]

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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 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
GJB2NM_004004.6 linkuse as main transcriptc.341A>G p.Glu114Gly missense_variant 2/2 ENST00000382848.5
GJB2XM_011535049.3 linkuse as main transcriptc.341A>G p.Glu114Gly missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB2ENST00000382848.5 linkuse as main transcriptc.341A>G p.Glu114Gly missense_variant 2/21 NM_004004.6 P1
GJB2ENST00000382844.2 linkuse as main transcriptc.341A>G p.Glu114Gly missense_variant 1/1 P1

Frequencies

GnomAD3 genomes
AF:
0.00696
AC:
1059
AN:
152180
Hom.:
95
Cov.:
33
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.:
33
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.:
93
Cov.:
33
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.:
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
LINK: link

Submissions by phenotype

not specified Benign:8
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 14, 2014Glu114Gly 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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 14, 2014- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 27, 2016This 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. -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Autosomal recessive nonsyndromic hearing loss 1A Benign:4
Benign, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaMay 09, 2017- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingPars Genome LabJul 01, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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. -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 13, 2016Variant 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 submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 19, 2023- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncNov 29, 2017- -
Autosomal dominant nonsyndromic hearing loss 3A Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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 submitterclinical testingPars Genome LabJul 01, 2021- -
Ichthyosis, hystrix-like, with hearing loss Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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