rs119103223
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_022132.5(MCCC2):āc.803G>Cā(p.Arg268Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268G) has been classified as Uncertain significance.
Frequency
Consequence
NM_022132.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.803G>C | p.Arg268Thr | missense_variant, splice_region_variant | 8/17 | ENST00000340941.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC2 | ENST00000340941.11 | c.803G>C | p.Arg268Thr | missense_variant, splice_region_variant | 8/17 | 1 | NM_022132.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461704Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727164
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2023 | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site, deletes the last 19bp of exon 8 and introduces a premature termination codon (PMID: 16010683). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 268 of the MCCC2 protein (p.Arg268Thr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 11406611, 16835865). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1924). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at