chr1-119764385-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005518.4(HMGCS2):c.346C>T(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,080 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116H) has been classified as Uncertain significance.
Frequency
Consequence
NM_005518.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMGCS2 | NM_005518.4 | c.346C>T | p.Arg116Cys | missense_variant | 2/10 | ENST00000369406.8 | |
HMGCS2 | NM_001166107.1 | c.346C>T | p.Arg116Cys | missense_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMGCS2 | ENST00000369406.8 | c.346C>T | p.Arg116Cys | missense_variant | 2/10 | 1 | NM_005518.4 | P1 | |
HMGCS2 | ENST00000544913.2 | c.346C>T | p.Arg116Cys | missense_variant | 2/9 | 2 | |||
HMGCS2 | ENST00000476640.1 | n.242C>T | non_coding_transcript_exon_variant | 1/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251248Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135784
GnomAD4 exome AF: 0.0000800 AC: 117AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.0000811 AC XY: 59AN XY: 727234
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74356
ClinVar
Submissions by phenotype
3-hydroxy-3-methylglutaryl-CoA synthase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces arginine with cysteine at codon 116 of the HMGCS2 protein (p.Arg116Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200607527, ExAC 0.004%). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 203779). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at