rs760420191
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_022132.5(MCCC2):c.653C>T(p.Ala218Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,802 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. A218T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_022132.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.653C>T | p.Ala218Val | missense_variant | 7/17 | ENST00000340941.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC2 | ENST00000340941.11 | c.653C>T | p.Ala218Val | missense_variant | 7/17 | 1 | NM_022132.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251414Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135894
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461802Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727208
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2021 | Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 11170888, 22264772, 22642865, 17968484) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 218 of the MCCC2 protein (p.Ala218Val). This variant is present in population databases (rs760420191, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 17968484, 22264772; Invitae). ClinVar contains an entry for this variant (Variation ID: 575151). 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 MCCC2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala218 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22264772; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2021 | Variant summary: MCCC2 c.653C>T (p.Ala218Val) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251414 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.653C>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual with seizures, identified as part of newborn screening in whom the biochemical phenotype/fibroblast carboxylase activities were reported to be within reference range (example, Morscher_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at