rs1555937135
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate
The NM_000166.6(GJB1):c.304_306del(p.Glu102del) variant causes a inframe deletion change involving the alteration of a 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 inframe_deletion
NM_000166.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.34
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000166.6
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000166.6. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant X-71224010-AGAG-A is Pathogenic according to our data. Variant chrX-71224010-AGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 477594.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71224010-AGAG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.304_306del | p.Glu102del | inframe_deletion | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.304_306del | p.Glu102del | inframe_deletion | 2/2 | ||
GJB1 | XM_011530907.3 | c.304_306del | p.Glu102del | inframe_deletion | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.304_306del | p.Glu102del | inframe_deletion | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2003 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2018 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu102 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 8004109, 14627639, 17353473), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this variant disrupts the formation of gap junction plaques (PMID: 28071741). This variant has been observed to segregate in several families affected with X-linked Charcot-Marie-Tooth disease (CMTX) (PMID: 12707076, Invitae). ClinVar contains an entry for this variant (Variation ID: 477594). This variant is not present in population databases (ExAC no frequency). This variant, c.304_306delGAG, results in the deletion of 1 amino acid of the GJB1 protein (p.Glu102del), but otherwise preserves the integrity of the reading frame. - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at