rs119103221
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_022132.5(MCCC2):c.929C>G(p.Pro310Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
MCCC2
NM_022132.5 missense
NM_022132.5 missense
Scores
9
4
2
Clinical Significance
Conservation
PhyloP100: 4.73
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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_022132.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
?
Variant 5-71635176-C-G is Pathogenic according to our data. Variant chr5-71635176-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1922.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.929C>G | p.Pro310Arg | missense_variant | 10/17 | ENST00000340941.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC2 | ENST00000340941.11 | c.929C>G | p.Pro310Arg | missense_variant | 10/17 | 1 | NM_022132.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD3 exomes
AF:
AC:
1
AN:
251434
Hom.:
AF XY:
AC XY:
1
AN XY:
135888
Gnomad AFR exome
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GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ExAC
?
AF:
AC:
1
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 310 of the MCCC2 protein (p.Pro310Arg). This variant is present in population databases (rs119103221, gnomAD 0.006%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 11181649, 22642865; Invitae). ClinVar contains an entry for this variant (Variation ID: 1922). 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. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 11181649). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 31, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 13, 2021 | - - |
Autism spectrum disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Gene Friend Way, National Innovation Center | Jul 28, 2023 | 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency involves mutations in the MCCC1 or MCCC2 genes and impaired leucine metabolism. This missense change has been confirmed to affect MCCC2 function and can be observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 11181649). Mutations in MCCC2 had been found to be associated with ASD (PMID: 31209396). - |
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
Uncertain
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
Uncertain
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
MutPred
0.90
.;Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);.;
MVP
MPC
0.54
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at