rs144717157

chrX-71223942-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000166.6(GJB1):c.235C>T(p.Leu79=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 220932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223942-C-T is described in Lovd as [Likely_benign]. Variant chrX-71223942-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 55 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.235C>T	p.Leu79=	synonymous_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.235C>T	p.Leu79=	synonymous_variant	2/2
GJB1	XM_011530907.3	c.235C>T	p.Leu79=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.235C>T	p.Leu79=	synonymous_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 205 AN: 111161 Hom.: 0 Cov.: 22 AF XY: 0.00165 AC XY: 55 AN XY: 33393

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

GnomAD3 exomes AF: 0.00237 AC: 396 AN: 167208 Hom.: 1 AF XY: 0.00216 AC XY: 117 AN XY: 54224

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 SAS 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

Gnomad4 AFR exome AF: 0.000494

Gnomad4 AMR exome AF: 0.000817

Gnomad4 ASJ exome AF: 0.00904

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00496

Gnomad4 NFE exome AF: 0.00268

Gnomad4 OTH exome AF: 0.00183

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

Gnomad4 AFR AF: 0.000261

Gnomad4 AMR AF: 0.000383

Gnomad4 ASJ AF: 0.00944

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00400

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00197

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, flagged submission	literature only	Inherited Neuropathy Consortium	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2016	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. -

Dejerine-Sottas disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2014

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

GJB1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.6
Dann	Benign	0.72

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

Other links and lift over

dbSNP: rs144717157; hg19: chrX-70443792;