Variant chrX-71223642-CTTTCCACCCCAGCTTTCTGACAGCTTGCTTCATGGCTGGTGTTTTGCAGGTGTGAATGAGGCAGGATGAACTGGACAGGTTTGTACACCTTGCTCAGTGGCGTGAACCGGCATTCTACTGCCATTGGCCGAGTATGGCTCTCGGTCATCTTCATCTTCAGAATCATGGTGCTGGTGGTGGCTGCAGAGAGTGTGTGGGGTGATGAGAAATCTTCCTTCATCTGCAACACACTCCAGCCTGGCTGCAACAGCGTTTGCTATGACCAATTCTTCCCCATCTCCCATGTGCGGCTGTGGTCCCTGCAGCTCATCCTAG-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000166.6(GJB1):c.-16-35_264del variant causes a splice acceptor, coding sequence, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 22)

Consequence

GJB1
NM_000166.6 splice_acceptor, coding_sequence, 5_prime_UTR, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.842

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-71223642-CTTTCCACCCCAGCTTTCTGACAGCTTGCTTCATGGCTGGTGTTTTGCAGGTGTGAATGAGGCAGGATGAACTGGACAGGTTTGTACACCTTGCTCAGTGGCGTGAACCGGCATTCTACTGCCATTGGCCGAGTATGGCTCTCGGTCATCTTCATCTTCAGAATCATGGTGCTGGTGGTGGCTGCAGAGAGTGTGTGGGGTGATGAGAAATCTTCCTTCATCTGCAACACACTCCAGCCTGGCTGCAACAGCGTTTGCTATGACCAATTCTTCCCCATCTCCCATGTGCGGCTGTGGTCCCTGCAGCTCATCCTAG-C is Pathogenic according to our data. Variant chrX-71223642-CTTTCCACCCCAGCTTTCTGACAGCTTGCTTCATGGCTGGTGTTTTGCAGGTGTGAATGAGGCAGGATGAACTGGACAGGTTTGTACACCTTGCTCAGTGGCGTGAACCGGCATTCTACTGCCATTGGCCGAGTATGGCTCTCGGTCATCTTCATCTTCAGAATCATGGTGCTGGTGGTGGCTGCAGAGAGTGTGTGGGGTGATGAGAAATCTTCCTTCATCTGCAACACACTCCAGCCTGGCTGCAACAGCGTTTGCTATGACCAATTCTTCCCCATCTCCCATGTGCGGCTGTGGTCCCTGCAGCTCATCCTAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2857643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
GJB1	NM_000166.6 linkuse as main transcript	c.-16-35_264del	splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3 linkuse as main transcript	c.-16-35_264del	splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/2
GJB1	XM_011530907.3 linkuse as main transcript	c.-16-35_264del	splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.-16-35_264del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 19, 2023

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with GJB1-related conditions. This variant results in the deletion of part of exon 2 (c.-16-35_264del) of the GJB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GJB1 are known to be pathogenic (PMID: 11266688). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

No publications associated with this variant yet.