X-71223168-C-G

Variant names:

• chrX-71223168-C-G
• rs1060501001
• NM_001097642.3:c.-16-524C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001097642.3(GJB1):​c.-16-524C>G variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 22)
• Consequence: GJB1 NM_001097642.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.82
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71223168-C-G is Pathogenic according to our data. Variant chrX-71223168-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406227.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_001097642.3	c.-16-524C>G		intron_variant	Intron 1 of 1		NP_001091111.1
GJB1	NM_001440770.1	c.-17+402C>G		intron_variant	Intron 2 of 2		NP_001427699.1
GJB1	NM_000166.6	c.-184C>G		upstream_gene_variant		ENST00000361726.7	NP_000157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.-184C>G		upstream_gene_variant		1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the GJB1 gene. It does not change the encoded amino acid sequence of the GJB1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 24078732; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.-184C>G or c.-540C>G. ClinVar contains an entry for this variant (Variation ID: 406227). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Jun 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

No data available from control populations to assess the frequency of this variant; Other regulatory variants in GJB1 have been reported in the Human Gene Mutation Database in individuals with CMT (Stenson et al., 2014).; This variant is not expected to alter the ATG initiation codon. In the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown.; This variant is associated with the following publications: (PMID: 24078732) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Benign	0.82
PhyloP100		3.8
PromoterAI		-0.0054	Neutral
Mutation Taster		=14/86	disease causing

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: rs1060501001; hg19: chrX-70443018;