rs200774406
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_000166.6(GJB1):c.712C>T(p.Arg238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,208,174 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.712C>T | p.Arg238Cys | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.712C>T | p.Arg238Cys | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.712C>T | p.Arg238Cys | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.712C>T | p.Arg238Cys | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000897 AC: 1AN: 111500Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33676
GnomAD3 exomes AF: 0.0000451 AC: 8AN: 177357Hom.: 0 AF XY: 0.0000476 AC XY: 3AN XY: 63023
GnomAD4 exome AF: 0.0000119 AC: 13AN: 1096619Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 5AN XY: 362117
GnomAD4 genome AF: 0.00000896 AC: 1AN: 111555Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33741
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 07, 2020 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Charcot-Marie-Tooth Neuropathy X Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 2017 | 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in an individual affected with Charcot Marie Tooth disease type 1 (PMID: 23838279). This variant is present in population databases (rs200774406, ExAC 0.03%). This sequence change replaces arginine with cysteine at codon 238 of the GJB1 protein (p.Arg238Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at