rs119103226
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_022132.5(MCCC2):c.838G>T(p.Asp280Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,120 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
MCCC2
NM_022132.5 missense
NM_022132.5 missense
Scores
11
2
2
Clinical Significance
Conservation
PhyloP100: 9.93
Genes affected
MCCC2 (HGNC:6937): (methylcrotonyl-CoA carboxylase subunit 2) This gene encodes the small subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a domain CoA carboxyltransferase N-terminal (size 257) in uniprot entity MCCB_HUMAN there are 45 pathogenic changes around while only 2 benign (96%) in NM_022132.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.965
PP5
?
Variant 5-71634977-G-T is Pathogenic according to our data. Variant chr5-71634977-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC2 | NM_022132.5 | c.838G>T | p.Asp280Tyr | missense_variant | 9/17 | ENST00000340941.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC2 | ENST00000340941.11 | c.838G>T | p.Asp280Tyr | missense_variant | 9/17 | 1 | NM_022132.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251424Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135890
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727210
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74474
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 280 of the MCCC2 protein (p.Asp280Tyr). This variant is present in population databases (rs119103226, gnomAD 0.09%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 17968484, 22030835, 22150417, 28018443). ClinVar contains an entry for this variant (Variation ID: 1927). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University | May 13, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
MVP
MPC
0.58
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at