MCCC2

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

Basic information

Region (hg38): 5:71579530-71658706

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 (547 variants)
• not provided (139 variants)
• Methylcrotonyl-CoA carboxylase deficiency (45 variants)
• not specified (43 variants)
• Inborn genetic diseases (24 variants)
• MCCC2-related condition (8 variants)
• See cases (1 variants)
• Autism spectrum disorder (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	123	4	129
missense	4	39	138	3		184
nonsense	13	15		1		29
start loss						0
frameshift	17	13	2			32
inframe indel			1			1
splice donor/acceptor (+/-2bp)	3	28				31
splice region		1	14	28	2	45
non coding		1	37	75	55	168
Total	37	96	180	202	59

Highest pathogenic variant AF is 0.0000460

Variants in MCCC2

This is a list of pathogenic ClinVar variants found in the MCCC2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-71587090-A-T			Benign (Jun 19, 2018)
5-71587123-C-G			Benign (Jun 19, 2018)
5-71587242-G-A			Likely benign (Apr 09, 2019)
5-71587309-A-G		3-methylcrotonyl-CoA carboxylase 2 deficiency	Benign (Jun 19, 2021)
5-71587388-G-A		3-methylcrotonyl-CoA carboxylase 2 deficiency • not specified	Conflicting classifications of pathogenicity (Jan 13, 2018)
5-71587406-C-G		not specified	Likely benign (Jul 05, 2017)
5-71587428-GTGGGCCGTCCTGAGGTTAGCCCTGCGGCCGTGTGCCCGCGCCTCTCCCGCCGGGCCGCGCGCCTA-G		3-methylcrotonyl-CoA carboxylase 2 deficiency	Pathogenic (Aug 23, 2023)
5-71587431-G-C			Uncertain significance (Jan 21, 2014)
5-71587434-C-A		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Feb 10, 2023)
5-71587438-C-T		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Nov 25, 2023)
5-71587450-C-T		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Jun 22, 2022)
5-71587457-C-T			Uncertain significance (Jun 01, 2016)
5-71587463-C-G		3-methylcrotonyl-CoA carboxylase 2 deficiency	Uncertain significance (May 13, 2022)
5-71587470-C-T		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Mar 24, 2023)
5-71587476-C-G		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Nov 20, 2023)
5-71587479-C-G		not specified • 3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Feb 19, 2020)
5-71587479-C-T		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Mar 08, 2022)
5-71587482-G-C		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Nov 29, 2022)
5-71587483-C-T		3-methylcrotonyl-CoA carboxylase 2 deficiency • Inborn genetic diseases	Uncertain significance (Jan 20, 2023)
5-71587485-G-C		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely benign (Jul 01, 2022)
5-71587486-C-T		Inborn genetic diseases	Uncertain significance (Jun 23, 2023)
5-71587493-A-C		3-methylcrotonyl-CoA carboxylase 2 deficiency • Inborn genetic diseases	Conflicting classifications of pathogenicity (May 08, 2023)
5-71587493-A-G		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely pathogenic (Jan 29, 2024)
5-71587493-AT-A		3-methylcrotonyl-CoA carboxylase 2 deficiency	Pathogenic (May 28, 2023)
5-71587494-TC-T		3-methylcrotonyl-CoA carboxylase 2 deficiency	Likely pathogenic (Feb 20, 2023)

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

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