rs137852810
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000747.3(CHRNB1):c.865G>A(p.Val289Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V289A) has been classified as Pathogenic.
Frequency
Consequence
NM_000747.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNB1 | NM_000747.3 | c.865G>A | p.Val289Met | missense_variant | 8/11 | ENST00000306071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNB1 | ENST00000306071.7 | c.865G>A | p.Val289Met | missense_variant | 8/11 | 1 | NM_000747.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 2A Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 09, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNB1 function (PMID: 8872460). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 18372). This missense change has been observed in individuals with autosomal dominant slow-channel congenital myasthenic syndrome (PMID: 8872460, 20562457, 27391121). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 289 of the CHRNB1 protein (p.Val289Met). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2024 | Published functional studies demonstrate a damaging effect (pathologic channel opening) (PMID: 8872460); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27391121, 20562457, 8872460, 32895905) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 16, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at