rs770116247

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BP4

The NM_000166.6(GJB1):c.565G>A(p.Val189Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,204,597 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V189G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000012 ( 0 hom. 8 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.86

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 hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000166.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-71224273-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3775502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GJB1	NM_000166.6 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	2/2
GJB1	XM_011530907.3 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

109468

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31776

show subpopulations

Gnomad AFR

AF:

0.0000668

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

180704

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65952

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1095129

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

361835

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000924

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000274

AC:

AN:

109468

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31776

show subpopulations

Gnomad4 AFR

AF:

0.0000668

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:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2019

The p.V189I variant (also known as c.565G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 565. The valine at codon 189 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease X-linked dominant 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.030

Cadd

Benign

Dann

Benign

0.46

DEOGEN2

Uncertain

0.61

D;D;D;D;D

FATHMM_MKL

Uncertain

0.80

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

-0.41

N;N;N;N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.17

N;.;N;.;N

REVEL

Uncertain

0.51

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

1.0

T;.;T;.;T

Polyphen

0.037

B;B;B;B;B

Vest4

0.63

MutPred

0.55

Loss of catalytic residue at V189 (P = 0.0099);Loss of catalytic residue at V189 (P = 0.0099);Loss of catalytic residue at V189 (P = 0.0099);Loss of catalytic residue at V189 (P = 0.0099);Loss of catalytic residue at V189 (P = 0.0099);

MVP

0.98

MPC

0.63

ClinPred

0.021

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.072

gMVP

0.89

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