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rs35887622

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.101T>G(p.Met34Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M34T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

GJB2
NM_004004.6 missense

Scores

11
6
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.06
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 Pathogenic. 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 1 benign, 2 uncertain in NM_004004.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-20189481-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17000.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 13-20189481-A-C is Pathogenic according to our data. Variant chr13-20189481-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB2NM_004004.6 linkuse as main transcriptc.101T>G p.Met34Arg missense_variant 2/2 ENST00000382848.5
GJB2XM_011535049.3 linkuse as main transcriptc.101T>G p.Met34Arg missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB2ENST00000382848.5 linkuse as main transcriptc.101T>G p.Met34Arg missense_variant 2/21 NM_004004.6 P1
GJB2ENST00000382844.2 linkuse as main transcriptc.101T>G p.Met34Arg missense_variant 1/1 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeDec 16, 2022In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met34 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16077952, 22668073, 26117665; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. ClinVar contains an entry for this variant (Variation ID: 44722). This variant has not been reported in the literature in individuals affected with GJB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 34 of the GJB2 protein (p.Met34Arg). -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 20, 2021Reported in a patient with hearing loss in published literature (Putcha et al., 2007); however, clinical and molecular data were limited; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Splice predictors and evolutionary conservation suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25388846, 17666888, 31589614) -
Rare genetic deafness Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 19, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
Cadd
Pathogenic
32
Dann
Uncertain
0.98
DEOGEN2
Pathogenic
0.91
D;D;D
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.9
M;M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.5
D;D;.
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
0.98
D;D;D
Vest4
0.93
MutPred
0.98
Gain of methylation at M34 (P = 0.0182);Gain of methylation at M34 (P = 0.0182);Gain of methylation at M34 (P = 0.0182);
MVP
0.93
MPC
0.27
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.97
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.58
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.58
Position offset: -1

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: rs35887622; hg19: chr13-20763620; API