chr5-71604412-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_022132.5(MCCC2):c.568C>T(p.His190Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,966 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).
Frequency
Consequence
NM_022132.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.568C>T | p.His190Tyr | missense_variant | Exon 6 of 17 | ENST00000340941.11 | NP_071415.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727236
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:2Uncertain:1
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This variant is interpreted as Likely Pathogenic, for MCC2 deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/16010683). -
This sequence change replaces histidine with tyrosine at codon 190 of the MCCC2 protein (p.His190Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs773774134, ExAC 0.001%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 198252). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 16010683). This variant disrupts the p.His190 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been observed in individuals with MCCC2-related conditions (PMID: 16010683, 17968484), which suggests that this may be a clinically significant amino acid residue. 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 Pathogenic:2
The H190Y variant in the MCCC2 gene has been reported previously in association with 3-methylcrotonyl-CoA carboxylase deficiency, in an affected individual who was homozygous for the H190Y variant (Dantas et al., 2005). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The H190Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, and expression studies found that H190Y is associated with severely decreased 3-methylcrotonyl-CoA carboxylase activity (Dantas et al., 2005). Missense variants in the same codon (H190R) and nearby residues (R193C and R193H) have been reported in the Human Gene Mutation Database in association with 3-methylcrotonyl-CoA carboxylase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret H190Y as a pathogenic variant. -
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Methylcrotonyl-CoA carboxylase deficiency Pathogenic:1
Variant summary: MCCC2 c.568C>T (p.His190Tyr) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251464 control chromosomes. c.568C>T has been reported in the literature as a homozygous genotype in at-least one individual affected with a mild phenotype of Methylcrotonyl-CoA Carboxylase Deficiency (example, Dantas_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro (example, Dantas_2005). The most pronounced variant effect results in absence of normal 3-methylcrotonyl-CoA carboxylase (MCC) activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=1; P/LP, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
MCCC2-related disorder Pathogenic:1
The MCCC2 c.568C>T variant is predicted to result in the amino acid substitution p.His190Tyr. This variant was reported in the homozygous state in one mildly affected individual with 3-methylcrotonyl-CoA carboxylase deficiency (Dantas et al 2005. PubMed ID: 16010683). In an in vitro expression study, the p.His190Tyr substitution was reported to abolish enzyme activity (Dantas et al 2005. PubMed ID: 16010683). An alternative substitution of the same amino acid (p.His190Arg) was reported along with a second likely pathogenic MCCC2 variant in an individual with 3-methylcrotonyl-CoA carboxylase deficiency (Uematsu et al. 2007. PubMed ID: 17968484). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at