chr13-20189332-C-T

Variant summary

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

The NM_004004.6(GJB2):​c.250G>A​(p.Val84Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V84L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a helix (size 29) in uniprot entity CXB2_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) 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 chr13-20189332-C-G is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 13-20189332-C-T is Pathogenic according to our data. Variant chr13-20189332-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17036.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
GJB2NM_004004.6 linkc.250G>A p.Val84Met missense_variant Exon 2 of 2 ENST00000382848.5 NP_003995.2 P29033H9U1J4
GJB2XM_011535049.3 linkc.250G>A p.Val84Met missense_variant Exon 2 of 2 XP_011533351.1 P29033H9U1J4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB2ENST00000382848.5 linkc.250G>A p.Val84Met missense_variant Exon 2 of 2 1 NM_004004.6 ENSP00000372299.4 P29033
GJB2ENST00000382844.2 linkc.250G>A p.Val84Met missense_variant Exon 1 of 1 6 ENSP00000372295.1 P29033

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251338
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461806
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
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
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:4
Nov 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jun 02, 2023
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 08, 2016
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:3
Aug 21, 2023
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with hearing loss. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17660464) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

May 19, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with the variant resulting in gap junctions that are incapable of intercellular coupling (Matos et al., 2007); Not observed at a 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: 19101659, 25266519, 12865758, 25388846, 16222667, 24774219, 23668481, 9529365, 31160754, 30344259, 34440441, 34652575, 36100214, 26553399, 17660464, 31992338, 32067424) -

Sep 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Met). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 30344259, 31160754). ClinVar contains an entry for this variant (Variation ID: 17036). 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%. This variant disrupts the p.Val84 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11556849, 12172394, 16380907, 19235794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Progressive sensorineural hearing impairment Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Jun 08, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1
Feb 12, 2007
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

GJB2-related disorder Pathogenic:1
Jun 21, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The GJB2 c.250G>A variant is predicted to result in the amino acid substitution p.Val84Met. This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Plevova. 2018. PubMed ID: 30344259; Pandya. 2020. PubMed ID: 32067424; Table S2, Shen. 2019. PubMed ID: 31160754; Zhang. 2011. PubMed ID: 21366436; Cheng. 2005. PubMed ID: 16222667; Martínez-Saucedo. 2015. PubMed ID: 26553399; Primignani. 2009. PubMed ID: 19371219; Loeza-Becerra. 2014. PubMed ID: 24774219). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763471-C-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;D;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
.;.;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.6
H;H;H
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.0
D;D;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
D;D;D
Vest4
0.93
MutPred
0.97
Loss of glycosylation at S85 (P = 0.1298);Loss of glycosylation at S85 (P = 0.1298);Loss of glycosylation at S85 (P = 0.1298);
MVP
0.98
MPC
0.28
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.84
gMVP
0.95

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: rs104894409; hg19: chr13-20763471; API