ACOX2

protein-coding

acyl-CoA oxidase 2

Gene summary

The product of this gene belongs to the acyl-CoA oxidase family. It encodes the branched-chain acyl-CoA oxidase which is involved in the degradation of long branched fatty acids and bile acid intermediates in peroxisomes. Deficiency of this enzyme results in the accumulation of branched fatty acids and bile acid intermediates, and may lead to Zellweger syndrome, severe cognitive disability, and death in children. [provided by RefSeq, Mar 2009]

MANE transcript

NM_003500.4

Inheritance

ClinVar variants

P:7U:203B:91

Top phenotype

Bile acid synthesis defect, congenital, 6

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr3:58,505,136-58,537,283

External References & Databases

Ensembl (ENSG00000168306)

Transcript & Mutation Effects

hg38 • Region Span ~32.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital bile acid synthesis defect 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015015

Submitter: PanelApp Australia

congenital bile acid synthesis defect 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015015

Submitter: Ambry Genetics

congenital bile acid synthesis defect 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015015

Submitter: Labcorp Genetics (formerly Invitae)

congenital bile acid synthesis defect 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015015

Submitter: ClinGen

*ACOX2* was first reported in relation to autosomal recessive congenital bile acid synthesis defect 6 in 2016 (Vilarinho et al., PMID: 27647924). *ACOX2* encodes a branched-chain acyl-CoA oxidase that acts on C27 intermediate bile acid species in the peroxisome that generates C24 primary bile acids. The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of *ACOX2* enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between *ACOX2* and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive. This assertion has been upheld over time, and no contradictory evidence has yet emerged. This gene-disease pair was originally evaluated by the ClinGen Inborn Errors of Metabolism GCEP on December 10, 2021. It was reevaluated on July 12, 2024 (SOP 10). As a result of this reevaluation, the classification was increased from Moderate to Definitive with the addition of new cases and experimental evidence, including a new mouse model.

Clinical Genomic Database (CGD)

Bile acid synthesis defect, congenital, 6AR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal

Rationale: Individuals have been described with hepatic dysfunction, and avoidance of hepatotoxic agents and medical management (eg, with cholestyramine) has been described as beneficial

Refs: 27647924; 27884763

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACOX2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 211

not specifiedTotal: 117

ACOX2-related disorderTotal: 107

Congenital bile acid synthesis defect 6Total: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003500.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				68 clinvar	2 clinvar	70
missense		2 clinvar	187 clinvar	18 clinvar	3 clinvar	210
nonsense	1 clinvar		3 clinvar			4
start loss						0
frameshift		1 clinvar	6 clinvar			7
splice donor/acceptor (+/-2bp)		3 clinvar	7 clinvar			10
Total	1	6	203	86	5	301

Highest pathogenic variant AF is 0.00012204369

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 89 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003500.4	RefSeq	NP_003491.1	14	MANE Select
ENST00000302819.10	Ensembl	ENSP00000307697.5	14	MANE Select
ENST00000459701.6	Ensembl	ENSP00000418562.2	14	Standard
ENST00000459701.7	Ensembl	ENSP00000418562.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
27-Hydroxylase Deficiency
Bile Acid Biosynthesis

Biological Process

protein targeting to peroxisome
bile acid biosynthetic process
positive regulation of cell death
fatty acid beta-oxidation using acyl-CoA oxidase
lipid homeostasis

Molecular Function

acyl-CoA oxidase activity
signaling receptor binding
fatty acid binding
pristanoyl-CoA oxidase activity
3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA 24-hydroxylase activity

Cellular Component

peroxisome
peroxisomal matrix
cytosol
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302819
Coding exons: 14
Length: 32184
Individuals with no LoFs: 125082
Homozygous LoFs: 0
Heterozygous LoFs: 666
Defined: 125748
p: 0.00265

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.502	387	416	0.931	0.0000253	4427
Missense (PolyPhen)		118	134	0.88062		1429
Synonymous	0.521	159	168	0.949	0.0000105	1362
Loss of Function	2.16	21	34.8	0.604	0.00000157	393

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0014	0.0014	notable
Latino/Admixed American	0.00072	0.00072	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0.0088	0.0089	notable
European (Non-Finnish)	0.0028	0.0028	notable
South Asian	0.0029	0.0029	notable
Other	0.0024	0.0024	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Oxidizes the CoA esters of the bile acid intermediates di- and tri-hydroxycholestanoic acids. {ECO:0000269|PubMed:27884763}.;

Recessive Scores

pRec: 0.148

Intolerance Scores

LoFtool: 0.712
RVIS EVS: -0.57
RVIS percentile EVS: 18.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.175

Gene Damage Prediction

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