rs104894825

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000166.6(GJB1):c.704T>G(p.Phe235Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,208,238 control chromosomes in the GnomAD database, including 1 homozygotes. There are 144 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. F235L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., 67 hem., cov: 21)

Exomes 𝑓: 0.00029 ( 0 hom. 77 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:8O:1

Conservation

PhyloP100: 1.98

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 1
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
X-linked progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GJB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 184 pathogenic changes around while only 11 benign (94%) in NM_000166.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.

BP4

Computational evidence support a benign effect (MetaRNN=0.03338042).

BP6

Variant X-71224411-T-G is Benign according to our data. Variant chrX-71224411-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10450.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (309/111458) while in subpopulation AFR AF = 0.00949 (291/30648). AF 95% confidence interval is 0.0086. There are 1 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 67 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.704T>G	p.Phe235Cys	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.704T>G	p.Phe235Cys	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	NM_001440770.1 link	c.704T>G	p.Phe235Cys	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.704T>G	p.Phe235Cys	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

309

AN:

111403

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00952

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

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:

0.00201

GnomAD2 exomes

AF:

0.000727

AC:

129

AN:

177535

AF XY:

0.000411

show subpopulations

Gnomad AFR exome

AF:

0.00888

Gnomad AMR exome

AF:

0.000442

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000632

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.000286

AC:

314

AN:

1096780

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

AN XY:

362278

show subpopulations

African (AFR)

AF:

0.00970

AC:

256

AN:

26386

American (AMR)

AF:

0.000512

AC:

AN:

35142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.00

AC:

AN:

53893

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39991

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

841643

Other (OTH)

AF:

0.000565

AC:

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00277

AC:

309

AN:

111458

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

AN XY:

33654

show subpopulations

African (AFR)

AF:

0.00949

AC:

291

AN:

30648

American (AMR)

AF:

0.00133

AC:

AN:

10536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3511

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53029

Other (OTH)

AF:

0.00198

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.00308

ESP6500AA

AF:

0.00834

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000783

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:1Benign:2Other:1

May 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not specified

Benign:2

Jun 25, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 02, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23871722, 22771394, 15852376, 21291455, 27066513, 12951564, 27228968, 9361298, 30340945) -

Inborn genetic diseases

Uncertain:1

Jul 25, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F235C variant (also known as c.704T>G), located in coding exon 1 of the GJB1 gene, results from a T to G substitution at nucleotide position 704. The phenylalanine at codon 235 is replaced by cysteine, an amino acid with highly dissimilar properties.This variant, which occurs in the C-terminal domain, is purported to result in a gain of function activity and is associated with a severe and early onset form of Charcot-Marie-Tooth disease (Bone, LJ et al. Neurobiol Dis 1997;4:221-30, Kim, Y et al. Clin Genet 2012;81:142-149, Liang, GS et al. Ann Neurol 2005;57:749-754, Lin, GS et al. Ann NY Acad Sci 1999;883:481-4). This variant was previously reported in the SNPDatabase as rs104894825. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0% (0/503) total male alleles studied. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.16% (4/2443) total male alleles studied, having been observed in 0.7% (4/571) African American male alleles. This amino acid position is conserved in available mammalian species, but is not conserved from chicken down. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this variant remains unclear. -

Charcot-Marie-Tooth disease

Benign:1

Jun 28, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.20

T;T;T;T;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.60

.;.;.;.;T

MetaRNN

Benign

0.033

T;T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

0.34

N;N;N;N;N

PhyloP100

2.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.48

N;.;N;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.17

T;.;T;.;T

Sift4G

Benign

0.17

T;.;T;.;T

Polyphen

0.80

P;P;P;P;P

Vest4

0.72

MVP

0.89

MPC

1.3

ClinPred

0.038

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.78

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over