rs1057517976

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_004004.6(GJB2):c.146C>T(p.Ala49Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,612,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.84

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) in NM_004004.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.146C>T	p.Ala49Val	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.146C>T	p.Ala49Val	missense_variant	Exon 2 of 2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.146C>T	p.Ala49Val	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.146C>T	p.Ala49Val	missense_variant	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460046

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:2

Mar 29, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Dec 06, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A49V variant in the GJB2 gene has been reported previously in the heterozygous state and also in the presence of another GJB2 variant in Japanese individuals with hearing loss (Ohtsuka et al., 2003; Tsukada et al., 2010), although no family history or other clinical information was reported. The A49V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A49V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret A49V as a variant of uncertain significance. -

Jun 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB2 c.146C>T (p.Ala49Val) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 328300 control chromosomes, predominantly at a frequency of 0.00036 within the Japanese subpopulation (no homozygotes; gnomAD and jMorp databases; Tadaka_2021). The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (3.4e-04), strongly suggesting that the variant is benign. c.146C>T has been reported in the literature in individuals affected with Hearing Loss (e.g., Ohtsuka_2003, Tsudaka_2010, Nishio_2015), however withouth strong evidence for causality in all cases (e.g., lack of co-segregation and co-occurrence data). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25788563, 12560944, 20497192, 33179747). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:1

Nov 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 49 of the GJB2 protein (p.Ala49Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hearing loss (PMID: 12560944, 20497192, 25788563). ClinVar contains an entry for this variant (Variation ID: 372771). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

.;.;T

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;.

REVEL

Uncertain

0.48

Sift

Uncertain

0.0090

D;D;.

Sift4G

Uncertain

0.0070

D;D;.

Polyphen

0.68

P;P;P

Vest4

0.14

MutPred

0.60

Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);

MVP

0.94

MPC

0.043

ClinPred

0.89

GERP RS

5.2

Varity_R

0.39

gMVP

0.78

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