rs144717157

Variant names:

• chrX-71223942-C-T
• rs144717157
• NM_000166.6:c.235C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000166.6(GJB1):​c.235C>T​(p.Leu79Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00246 in 1,203,224 control chromosomes in the GnomAD database, including 3 homozygotes. There are 924 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 55 hem., cov: 22)
  • Exomes 𝑓: 0.0025 (3 hom. 869 hem.)
• Consequence: GJB1 NM_000166.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:11
• Conservation: PhyloP100: 5.00
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-71223942-C-T is Benign according to our data. Variant chrX-71223942-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00184 (205/111213) while in subpopulation NFE AF = 0.00266 (141/52947). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 55 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	NP_000157.1
	GJB1	NM_001097642.3		c.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	NP_001091111.1
	GJB1	NM_001440770.1		c.235C>T	p.Leu79Leu	synonymous	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	ENSP00000354900.6
	GJB1	ENST00000374029.2	TSL:5	c.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.235C>T	p.Leu79Leu	synonymous	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 205 AN: 111161 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000384

Gnomad ASJ AF: 0.00944

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00400

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00200

GnomAD2 exomes AF: 0.00237 AC: 396 AN: 167208 AF XY: 0.00216

Gnomad AFR exome AF: 0.000408

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00721

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00463

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00252 AC: 2752 AN: 1092011 Hom.: 3 Cov.: 32 AF XY: 0.00243 AC XY: 869 AN XY: 358185

African (AFR) AF: 0.000494 AC: 13 AN: 26335

American (AMR) AF: 0.000817 AC: 28 AN: 34292

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 174 AN: 19255

East Asian (EAS) AF: 0.00 AC: 0 AN: 30022

South Asian (SAS) AF: 0.00 AC: 0 AN: 53178

European-Finnish (FIN) AF: 0.00496 AC: 199 AN: 40151

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4130

European-Non Finnish (NFE) AF: 0.00268 AC: 2252 AN: 838776

Other (OTH) AF: 0.00183 AC: 84 AN: 45872

GnomAD4 genome AF: 0.00184 AC: 205 AN: 111213 Hom.: 0 Cov.: 22 AF XY: 0.00164 AC XY: 55 AN XY: 33455

African (AFR) AF: 0.000261 AC: 8 AN: 30637

American (AMR) AF: 0.000383 AC: 4 AN: 10439

Ashkenazi Jewish (ASJ) AF: 0.00944 AC: 25 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3502

South Asian (SAS) AF: 0.00 AC: 0 AN: 2625

European-Finnish (FIN) AF: 0.00400 AC: 24 AN: 5996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00266 AC: 141 AN: 52947

Other (OTH) AF: 0.00197 AC: 3 AN: 1522

Alfa AF: 0.00359 Hom.: 27

Bravo AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Charcot-Marie-Tooth disease X-linked dominant 1 Benign:3

Apr 27, 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.

Sep 27, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Dec 22, 2016

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.

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: literature only

Dejerine-Sottas disease Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Inborn genetic diseases Benign:1

Oct 21, 2014

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB1-related disorder Benign:1

Jun 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.6
DANN	Benign	0.72
PhyloP100		5.0
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs144717157; hg19: chrX-70443792;