MCCC2

Chr 5AR

methylcrotonyl-CoA carboxylase subunit 2

Also known as: MCCB, MCCCbeta

NCBI Gene: 64087 ENSG00000131844 UniProt: Q9HCC0 OMIM: 609014

The protein functions as the small subunit of 3-methylcrotonyl-CoA carboxylase, which catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA in leucine catabolism within the mitochondrial matrix. Mutations cause 3-methylcrotonyl-CoA carboxylase 2 deficiency through autosomal recessive inheritance, resulting in impaired leucine breakdown and 3-methylcrotonylglycinuria.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

3-Methylcrotonyl-CoA carboxylase 2 deficiencyMIM #210210

UniProt3-methylcrotonoyl-CoA carboxylase 2 deficiency

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · 3-methylcrotonyl-CoA carboxylase deficiency · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.90

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 2.04

OE 0.63 (0.45–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.31Z-score

OE missense 0.95 (0.86–1.05)

298 obs / 313.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.45–0.90)

0≤0.351.4

Missense OE?0.95 (0.86–1.05)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 22 / 35.0Missense obs/exp: 298 / 313.2Syn Z: 0.03

Background carrier burden — how many people carry a rare variant somewhere in MCCC2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

756 rare PASS variants

Rare truncating (LoF)

1 in 940

143 rare PASS variants

Rare synonymous (reference)

1 in 140

265 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MCCC2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 99	1 in 1,000
South Asian	~43k	1 in 76	1 in 650
Remaining (unassigned)	~30k	1 in 73	1 in 1,500
European (Finnish)	~27k	1 in 180	1 in 2,400
Admixed American	~22k	1 in 74	1 in 1,100
African / African American	~21k	1 in 61	1 in 750
East Asian	~20k	1 in 81	1 in 540
Ashkenazi Jewish	~13k	1 in 280	none seen
Middle Eastern	~2,884	1 in 81	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 17 coding exons well covered in gnomAD exomes; exons 2, 17 marginal. Genomes: all 17.? see exons ↓