MCCC2

methylcrotonyl-CoA carboxylase subunit 2, the group of Methylcrotonyl-CoA carboxylase subunits

Basic information

Region (hg38): 5:71579531-71658706

Links

ENSG00000131844

∙ NCBI:64087 ∙ OMIM:609014 ∙ HGNC:6937 ∙ Uniprot:Q9HCC0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

3-methylcrotonyl-CoA carboxylase deficiency (Supportive), mode of inheritance: AR
3-methylcrotonyl-CoA carboxylase deficiency (Definitive), mode of inheritance: AR
3-methylcrotonyl-CoA carboxylase 2 deficiency (Definitive), mode of inheritance: AR
3-methylcrotonyl-CoA carboxylase 2 deficiency (Strong), mode of inheritance: AR
3-methylcrotonyl-CoA carboxylase 2 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
3-Methylcrotonyl-CoA carboxylase 2 deficiency	AR	Biochemical	Therapy may not be necessary/effective in some individuals, but medical (eg, carnitine, glycine) and dietary (eg, low protein, leucine restricted) therapy may be beneficial in some individuals; Precautions in the setting of stressors such as viral illnesses may be beneficial	Biochemical; Neurologic	7128647; 1293382; 8598650; 8831079; 9544913; 11181649; 11170888; 15877210; 16835865; 17968484; 22030835; 22264772; 22642865; 25356967

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MCCC2 gene.

3-methylcrotonyl-CoA_carboxylase_2_deficiency (657 variants)
not_provided (109 variants)
Methylcrotonyl-CoA_carboxylase_deficiency (63 variants)
not_specified (56 variants)
Inborn_genetic_diseases (47 variants)
MCCC2-related_disorder (32 variants)
Spinal_muscular_atrophy,_type_IV (1 variants)
Autism_spectrum_disorder (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MCCC2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000022132.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			16 clinvar	155 clinvar	2 clinvar	173
missense	6 clinvar	71 clinvar	197 clinvar	7 clinvar		281
nonsense	14 clinvar	28 clinvar				42
start loss	1					1
frameshift	25 clinvar	23 clinvar	1 clinvar			49
splice donor/acceptor (+/-2bp)	5 clinvar	36 clinvar	1 clinvar			42
Total	51	158	215	162	2

Highest pathogenic variant AF is 0.000670395

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MCCC2	protein_coding	protein_coding	ENST00000340941	17	71417

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.51e-11	0.937	125674	0	74	125748	0.000294

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.306	298	313	0.951	0.0000164	3640
Missense in Polyphen		122	137.71	0.88591		1633
Synonymous	0.0302	112	112	0.996	0.00000607	1097
Loss of Function	2.04	22	35.0	0.628	0.00000199	409

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000724	0.000724
Ashkenazi Jewish	0.00	0.00
East Asian	0.000598	0.000544
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000237	0.000237
Middle Eastern	0.000598	0.000544
South Asian	0.000490	0.000490
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

Function: FUNCTION: Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3- methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism. {ECO:0000269|PubMed:17360195}.;
Disease: DISEASE: 3-methylcrotonoyl-CoA carboxylase 2 deficiency (MCC2D) [MIM:210210]: An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3- hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. {ECO:0000269|PubMed:11170888, ECO:0000269|PubMed:11181649, ECO:0000269|PubMed:11406611, ECO:0000269|PubMed:16010683, ECO:0000269|PubMed:17968484, ECO:0000269|PubMed:21071250, ECO:0000269|PubMed:22150417, ECO:0000269|PubMed:22264772, ECO:0000269|PubMed:22642865, ECO:0000269|PubMed:25382614, ECO:0000269|PubMed:27601257}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Valine, leucine and isoleucine degradation - Homo sapiens (human);3-Methylglutaconic Aciduria Type I;Valine, Leucine and Isoleucine Degradation;2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency;Isovaleric Aciduria;3-Methylcrotonyl Coa Carboxylase Deficiency Type I;Propionic Acidemia;Maple Syrup Urine Disease;3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency;Isobutyryl-coa dehydrogenase deficiency;3-hydroxyisobutyric aciduria;3-hydroxyisobutyric acid dehydrogenase deficiency;Isovaleric acidemia;Methylmalonate Semialdehyde Dehydrogenase Deficiency;Methylmalonic Aciduria;3-Methylglutaconic Aciduria Type IV;3-Methylglutaconic Aciduria Type III;Beta-Ketothiolase Deficiency;Biotin transport and metabolism;Branched-chain amino acid catabolism;Metabolism of amino acids and derivatives;leucine degradation;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Valine, leucine and isoleucine degradation;Valine Leucine Isoleucine degradation (Consensus)

Recessive Scores

pRec: 0.180

Intolerance Scores

loftool: 0.206
rvis_EVS: -0.22
rvis_percentile_EVS: 37.43

Haploinsufficiency Scores

pHI: 0.0357
hipred: N
hipred_score: 0.237
ghis: 0.501

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.977

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

Gene name: Mccc2
Phenotype

Gene ontology

Biological process: leucine catabolic process;biotin metabolic process;coenzyme A metabolic process;protein heterooligomerization
Cellular component: 3-methylcrotonyl-CoA carboxylase complex, mitochondrial;mitochondrion;mitochondrial matrix;cytosol;methylcrotonoyl-CoA carboxylase complex
Molecular function: methylcrotonoyl-CoA carboxylase activity;protein binding;ATP binding