X-71224395-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4BS1BS2

The NM_000166.6(GJB1):c.688C>T(p.Arg230Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,208,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 74 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).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.00016 ( 0 hom. 70 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:5

Conservation

PhyloP100: 1.07

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 Benign. Variant got -7 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

BP4

Computational evidence support a benign effect (MetaRNN=0.2892338).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000224 (25/111543) while in subpopulation AMR AF= 0.000665 (7/10531). AF 95% confidence interval is 0.000312. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.688C>T	p.Arg230Cys	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.688C>T	p.Arg230Cys	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.688C>T	p.Arg230Cys	missense_variant	Exon 2 of 2		XP_011529209.1	P08034A0A654ICJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.688C>T	p.Arg230Cys	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

111543

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33695

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000665

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00427

Gnomad NFE

AF:

0.000264

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.000112

AC:

AN:

179254

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

64464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000728

Gnomad SAS exome

AF:

0.000215

Gnomad FIN exome

AF:

0.0000675

Gnomad NFE exome

AF:

0.000137

Gnomad OTH exome

AF:

0.000676

GnomAD4 exome

AF:

0.000163

AC:

179

AN:

1096710

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

AN XY:

362228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000204

Gnomad4 FIN exome

AF:

0.0000251

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000224

AC:

AN:

111543

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33695

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.000665

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000264

Gnomad4 OTH

AF:

0.00134

Alfa

AF:

0.0000956

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Pathogenic:1Benign:1

Jan 22, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2013

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

pathogenic in males not in females -

not provided

Uncertain:1

Jun 13, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 26542351) -

not specified

Benign:1

Feb 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

May 27, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease X-linked dominant 1

Benign:1

Apr 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;T;T;T

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.92

.;.;.;.;D

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

0.34

N;N;N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.31

N;.;N;.;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.027

D;.;D;.;D

Sift4G

Benign

0.077

T;.;T;.;T

Polyphen

0.99

D;D;D;D;D

Vest4

0.090

MVP

0.99

MPC

1.3

ClinPred

0.048

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.85

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