rs773846324

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID:17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6904209/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 2.04

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.

PM2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.677T>G	p.Val226Gly	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.677T>G	p.Val226Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.677T>G	p.Val226Gly	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.677T>G	p.Val226Gly	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247688

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460126

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000835

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2017	The p.Val226Gly variant in GJB2 has been reported in the heterozygous state in o ne individual with hearing loss (Putcha 2007). This variant has been identified in 1/11448 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs773846324). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Val226Gly variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2017	- -

Nonsyndromic genetic hearing loss

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 26, 2023

The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (less than or equal to 0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID: 17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 24, 2021

This sequence change replaces valine with glycine at codon 226 of the GJB2 protein (p.Val226Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs773846324, ExAC 0.009%). This variant has been observed in individual(s) with deafness (PMID: 20201936; Invitae). ClinVar contains an entry for this variant (Variation ID: 447450). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.88

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

-0.34

N;N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

0.53

N;N;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

0.40

B;B;B

Vest4

0.80

MutPred

0.83

Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);

MVP

0.53

MPC

0.050

ClinPred

0.23

GERP RS

4.8

Varity_R

0.18

gMVP

0.88

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