chrX-71223181-G-T

Position:

• chrX-71223181-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000675609.1(GJB1):​c.-165-6G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 ENST00000675609.1 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 8.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_001097642.3	c.-16-511G>T		intron_variant
GJB1	XM_011530907.3	c.-17+415G>T		intron_variant
GJB1	NM_000166.6			upstream_gene_variant		ENST00000361726.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7			upstream_gene_variant		1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

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 individuals with clinical features of Charcot-Marie-Tooth disease (Invitae). It has also been observed to segregate with disease in related individuals. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

GJB1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

The GJB1 c.-171G>T variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. It is documented as a variant of uncertain significance in ClinVar and reported to segregate with affected status in a family tested by Invitae (https://preview.ncbi.nlm.nih.gov/clinvar/variation/2033849/). One alternate pre-coding change at this same nucleotide (c.-171G>C), as well as nearby up and downstream variants in this region (c.-170T>G, c.-172T>C, c.-173T>C, c.-173T>G), have also been reported as causative for X-linked dominant Charcot-Marie-Tooth neuropathy type 1, and show strong segregation in affected family members (Houlden et al. 2004. PubMed ID: 15470753; Fuxman Bass et al. 2015. PubMed ID: 25910213; Tsai et al. 2013. PubMed ID: 23827825; Ionasescu et al. 1996. PubMed ID: 8757034; Human Gene Mutation Database). These data indicate this is a pre-coding hotspot for pathogenic variation. Functional studies indicate that mutations in this region impact promoter activity and impair transcription factor binding (Houlden et al. 2004. PubMed ID: 15470753). Although we suspect this pre-coding change may be pathogenic, at this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	33
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70443031;