rs1057517519

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.59T>C(p.Ile20Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.26

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 19) in uniprot entity CXB2_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_004004.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 13-20189523-A-G is Pathogenic according to our data. Variant chr13-20189523-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.59T>C	p.Ile20Thr	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.59T>C	p.Ile20Thr	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.59T>C	p.Ile20Thr	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.59T>C	p.Ile20Thr	missense_variant	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:2

Mar 22, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 09, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Nov 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a pathogenic GJB2 variant in individuals with nonsyndromic hearing loss, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 31370293, 11313763, 16380907); Published functional studies demonstrate a damaging effect: exhibited a reduction of ionic permeability (PMID: 16217030); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33096615, 24256046, 25388846, 11313763, 33105617, 16380907, 25401782, 12189487, 31370293, 16217030) -

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 20 of the GJB2 protein (p.Ile20Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 11313763, 12189487, 16380907). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 371766). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 16217030). For these reasons, this variant has been classified as Pathogenic. -

nonsyndromic sensorineural hearing loss

Pathogenic:1

Feb 19, 2021

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hearing loss

Pathogenic:1

Sep 11, 2008

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Aug 31, 2020

INGEBI, INGEBI / CONICET

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.59T>C, p.Ile20Thr variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. Computational evidence predicted a pathogenic effect of the mutation to the protein applying to PP3 rule (REVELscore: 0.931). This variant has been identified in trans with pathogenic variants and in homozygous state in at least 4 patients with hearing impairment meeting PM3_VeryStrong (PMID: 11313763, 12189487, 16380907, 25401782, Laboratory of Physiology and Genetics of Hearing, INGEBI internal data). Besides, homozygous p.Ile20Thr change segregated in two brothers with hearing loss applying to PP1_Supporting rule (Laboratory of Physiology and Genetics of Hearing, INGEBI internal data). Functional studies in HEK293 cells demonstrated that p.Ile20Thr mutant exhibited a reduction of ionic permeability by two-electrode patch clamp recording experiment (PMID: 16217030) meeting PS3_Moderate. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PP3, PM3_VeryStrong, PP1_Supporting, PS3_Moderate. -

Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1

Aug 09, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

.;.;T

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;M

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.5

D;D;.

REVEL

Pathogenic

0.93

Sift

Uncertain

0.020

D;D;.

Sift4G

Uncertain

0.025

D;D;.

Polyphen

0.96

D;D;D

Vest4

0.75

MutPred

0.97

Loss of stability (P = 0.007);Loss of stability (P = 0.007);Loss of stability (P = 0.007);

MVP

0.98

MPC

0.21

ClinPred

0.99

GERP RS

5.2

Varity_R

0.72

gMVP

0.90

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