rs104894814

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_000166.6(GJB1):c.658C>G(p.Arg220Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,207,684 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.594

Variant links:

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. 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 cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

GJB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6 linkuse as main transcript	c.658C>G	p.Arg220Gly	missense_variant	2/2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 linkuse as main transcript	c.658C>G	p.Arg220Gly	missense_variant	2/2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 linkuse as main transcript	c.658C>G	p.Arg220Gly	missense_variant	2/2		XP_011529209.1	P08034A0A654ICJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.658C>G	p.Arg220Gly	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33080

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1096806

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362388

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:

0.00000832

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000902

AC:

AN:

110878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33080

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 24, 2021	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 30, 2023

Variant summary: GJB1 c.658C>G (p.Arg220Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 180621 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.658C>G has been reported in the literature in individual(s) affected with features of Charcot-Marie-Tooth Disease X-linked dominant 1, without strong evidence for causality (example, Bone_1997). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie-Tooth disease X-linked dominant 1. Co-occurrences with other pathogenic variant(s) (PMP22 Duplication) have been reported in two siblings affected with neuromuscular dystrophy, providing supporting evidence for a benign role (Hodapp_2006). At least one publication reports experimental evidence evaluating an impact on protein function (Yum_2002). These results showed no damaging effect of this variant on protein expression in HeLa cells. The following publications have been ascertained in the context of this evaluation (PMID: 9361298, 16401743, 12460545). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Charcot-Marie-Tooth Neuropathy X

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces arginine with glycine at codon 220 of the GJB1 protein (p.Arg220Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth (CMT) disease (PMID: 16401743). 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 C0"). Experimental studies have shown that this missense change does not substantially affect GJB1 function (PMID: 12460545, 21280457). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2019

Identified in a patient with Charcot-Marie-Tooth disease (CMT) in published literature (Bone et al., 1997); Observed in two siblings in published literature (Hodapp et al., 2006) who had a different genetic etiology for the phenotype; Published functional studies demonstrate normal protein expression (Yum et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 12460545, 9361298, 16401743, 21280457) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.30

T;T;T;T;T

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.69

.;.;.;.;T

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Uncertain

-0.040

MutationAssessor

Benign

0.69

N;N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.1

N;.;N;.;N

REVEL

Uncertain

0.63

Sift

Benign

0.42

T;.;T;.;T

Sift4G

Benign

0.58

T;.;T;.;T

Polyphen

0.85

P;P;P;P;P

Vest4

0.50

MutPred

0.77

Loss of MoRF binding (P = 0.0728);Loss of MoRF binding (P = 0.0728);Loss of MoRF binding (P = 0.0728);Loss of MoRF binding (P = 0.0728);Loss of MoRF binding (P = 0.0728);

MVP

1.0

MPC

1.0

ClinPred

0.17

GERP RS

2.0

Varity_R

0.16

gMVP

0.94

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