rs864622215
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PS1_ModeratePM1PM5BP4
The NM_000166.6(GJB1):c.644G>A(p.Arg215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000073 in 1,096,602 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.644G>A | p.Arg215Gln | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.644G>A | p.Arg215Gln | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.644G>A | p.Arg215Gln | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.644G>A | p.Arg215Gln | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome AF: 0.00000730 AC: 8AN: 1096602Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 6AN XY: 362294
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 25, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 215 of the GJB1 protein (p.Arg215Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GJB1 function (PMID: 10234007). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg215 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8162049, 8816997, 9187667, 22464564). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at