rs753503984

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_000166.6(GJB1):c.637A>G(p.Ile213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000995 in 1,205,979 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 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). Synonymous variant affecting the same amino acid position (i.e. I213I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.00011 ( 0 hom. 36 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 2.32

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 Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000166.6

BP4

Computational evidence support a benign effect (MetaRNN=0.29209244).

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GJB1	NM_000166.6 linkuse as main transcript	c.637A>G	p.Ile213Val	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3 linkuse as main transcript	c.637A>G	p.Ile213Val	missense_variant	2/2
GJB1	XM_011530907.3 linkuse as main transcript	c.637A>G	p.Ile213Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.637A>G	p.Ile213Val	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000366

AC:

AN:

109361

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31825

show subpopulations

Gnomad AFR

AF:

0.0000335

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:

0.0000571

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000222

AC:

AN:

180398

Hom.:

AF XY:

0.0000307

AC XY:

AN XY:

65230

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000494

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

116

AN:

1096618

Hom.:

Cov.:

AF XY:

0.0000994

AC XY:

AN XY:

362260

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:

0.000138

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000366

AC:

AN:

109361

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31825

show subpopulations

Gnomad4 AFR

AF:

0.0000335

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:

0.0000571

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2017

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.17

Cadd

Benign

Dann

Benign

0.75

DEOGEN2

Uncertain

0.62

D;D;D;D;D

FATHMM_MKL

Uncertain

0.84

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

0.34

N;N;N;N;N

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.27

N;.;N;.;N

REVEL

Uncertain

0.53

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.94

T;.;T;.;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.071

MVP

0.99

MPC

0.64

ClinPred

0.043

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

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