rs199470444
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_000079.4(CHRNA1):c.280G>T(p.Gly94Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G94S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000079.4 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 |
---|---|---|---|---|---|---|---|
CHRNA1 | NM_000079.4 | c.280G>T | p.Gly94Cys | missense_variant | 4/9 | ENST00000348749.9 | |
CHRNA1 | NM_001039523.3 | c.355G>T | p.Gly119Cys | missense_variant | 5/10 | ||
CHRNA1 | XM_017003256.2 | c.376G>T | p.Gly126Cys | missense_variant | 4/9 | ||
CHRNA1 | XM_017003257.2 | c.301G>T | p.Gly101Cys | missense_variant | 3/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA1 | ENST00000348749.9 | c.280G>T | p.Gly94Cys | missense_variant | 4/9 | 1 | NM_000079.4 | P1 | |
ENST00000442996.1 | n.322-15119C>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251418Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135884
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727240
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74264
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2023 | Published functional studies demonstrate a damaging effect; specifically, in-vitro analysis have shown that the G94C variant leads to significantly reduced surface expression of the protein in AChR cultured cells; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14719537, 23679851, 22728938, 25305004, 25159927) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 09, 2019 | - - |
Lethal multiple pterygium syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 94 of the CHRNA1 protein (p.Gly94Cys). This variant is present in population databases (rs199470444, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital myasthenic syndrome in the compound heterozygous state (PMID: 22728938). This variant is also known as G74C. ClinVar contains an entry for this variant (Variation ID: 565596). 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 CHRNA1 protein function. Experimental studies have shown that this missense change affects CHRNA1 function (PMID: 22728938). 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