5-71652739-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_022132.5(MCCC2):āc.1559A>Cā(p.Tyr520Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,614,052 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 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.1559A>C | p.Tyr520Ser | missense_variant | 16/17 | ENST00000340941.11 | NP_071415.1 | |
MCCC2 | NM_001363147.1 | c.1445A>C | p.Tyr482Ser | missense_variant | 15/16 | NP_001350076.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251390Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727222
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 520 of the MCCC2 protein (p.Tyr520Ser). This variant is present in population databases (rs150327768, gnomAD 0.004%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency (PMID: 21071250; Invitae). ClinVar contains an entry for this variant (Variation ID: 467805). 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. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2024 | Variant summary: MCCC2 c.1559A>C (p.Tyr520Ser) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 2e-05 in 251390 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1559A>C has been reported in the literature in an individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (Nguyen_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21071250). ClinVar contains an entry for this variant (Variation ID: 467805). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Methylcrotonyl-CoA carboxylase deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at