5-71599672-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4
The NM_022132.5(MCCC2):c.295G>C(p.Glu99Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022132.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.295G>C | p.Glu99Gln | missense_variant | Exon 4 of 17 | ENST00000340941.11 | NP_071415.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251438Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135894
GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727170
GnomAD4 genome AF: 0.000151 AC: 23AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74372
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:6
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This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 99 of the MCCC2 protein (p.Glu99Gln). This variant is present in population databases (rs119103219, gnomAD 0.007%). This missense change has been observed in individual(s) with 3-Methylcrotonyl-CoA carboxylase deficiency (PMID: 11181649, 11406611, 22642865). ClinVar contains an entry for this variant (Variation ID: 1920). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCCC2 protein function. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 11181649). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
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The E99Q missense variant in the MCCC2 gene has been reported previously in association with3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Baumgartner et al., 2001; Grunert et al.,2012). In-vitro expression studies found that E99Q is associated with no detectable 3-MCC enzymeactivity (Baumgartner et al., 2001). The E99Q variant is not observed at a significant frequency inlarge population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). In summary, we interpret E99Q to be a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at