rs1555937015
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Moderate
The NM_000166.6(GJB1):c.53C>G(p.Thr18Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T18A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.53C>G | p.Thr18Ser | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.53C>G | p.Thr18Ser | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.53C>G | p.Thr18Ser | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.53C>G | p.Thr18Ser | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2017 | This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Family studies have indicated that this variant was not present in the parents of an individual with sensory and motor neuropathy, which suggests that it was de novo in that affected individual (Invitae). This sequence change replaces threonine with serine at codon 18 of the GJB1 protein (p.Thr18Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at