rs766591766
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_022132.5(MCCC2):c.1273A>G(p.Met425Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,102 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. M425I) has been classified as Uncertain significance.
Frequency
Consequence
NM_022132.5 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 |
---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.1273A>G | p.Met425Val | missense_variant | 14/17 | ENST00000340941.11 | |
MCCC2 | NM_001363147.1 | c.1159A>G | p.Met387Val | missense_variant | 13/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC2 | ENST00000340941.11 | c.1273A>G | p.Met425Val | missense_variant | 14/17 | 1 | NM_022132.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251466Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 03, 2021 | This sequence change replaces methionine with valine at codon 425 of the MCCC2 protein (p.Met425Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs766591766, ExAC 0.02%) but has not been reported in the literature in individuals with a MCCC2-related disease. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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"). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at