rs104894825

Positions:

chrX-71224411-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 -11 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=0.03338042).

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 id is 10450.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1, Benign=2}. Variant chrX-71224411-T-G is described in Lovd as [Likely_benign]. Variant chrX-71224411-T-G is described in Lovd as [Pathogenic].

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 male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 67 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6 linkuse as main transcript	c.704T>G	p.Phe235Cys	missense_variant	2/2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 linkuse as main transcript	c.704T>G	p.Phe235Cys	missense_variant	2/2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 linkuse as main transcript	c.704T>G	p.Phe235Cys	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.704T>G	p.Phe235Cys	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

309

AN:

111403

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

AN XY:

33589

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

GnomAD3 exomes

AF:

0.000727

AC:

129

AN:

177535

Hom.:

AF XY:

0.000411

AC XY:

AN XY:

63327

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 SAS 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

Gnomad4 AFR exome

AF:

0.00970

Gnomad4 AMR exome

AF:

0.000512

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:

0.0000154

Gnomad4 OTH exome

AF:

0.000565

GnomAD4 genome

AF:

0.00277

AC:

309

AN:

111458

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

AN XY:

33654

show subpopulations

Gnomad4 AFR

AF:

0.00949

Gnomad4 AMR

AF:

0.00133

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:

0.00198

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2020	This variant is associated with the following publications: (PMID: 23871722, 22771394, 15852376, 21291455, 27066513, 12951564, 27228968, 9361298, 30340945) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2014

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 28, 2020

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

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

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

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

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