ACAT2

protein-coding

acetyl-CoA acetyltransferase 2

Gene summary

The product of this gene is an enzyme involved in lipid metabolism, and it encodes cytosolic acetoacetyl-CoA thiolase. This gene shows complementary overlapping with the 3-prime region of the TCP1 gene in both mouse and human. These genes are encoded on opposite strands of DNA, as well as in opposite transcriptional orientation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

MANE transcript

NM_005891.3

Inheritance

ClinVar variants

U:61B:8

Top phenotype

Acetyl-CoA acetyltransferase-2 deficiency

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr6:159,762,045-159,779,112

External References & Databases

Ensembl (ENSG00000120437)

Transcript & Mutation Effects

hg38 • Region Span ~17.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acetyl-CoA acetyltransferase-2 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013548

Submitter: Ambry Genetics

acetyl-CoA acetyltransferase-2 deficiencyNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0013548

Submitter: ClinGen

No convincing evidence for a causal role for ACAT2 in acetyl-CoA acetyltransferase-2 deficiency has been reported. Two patients proposed to be affected with this disease have been reported (PMID: 6150136 and PMID: 20597). However, they were never investigated genetically, and later reviews highlight the incomplete and unproven nature of this diagnosis due to the evaluation of the enzyme only (PMID: 9607396). Although this gene-disease association is supported by its biochemical function and an animal model with preweaning lethality (PMID: 27626380), no reports have directly implicated the gene in humans. This gene-disease pair was originally evaluated by the FAO GCEP on 08/14/2018. It was reevaluated on 01/15/2021. As a result of this reevaluation, the classification did not change as no new information is contributing to the classification.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACAT2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 57

not providedTotal: 8

Acetyl-CoA acetyltransferase-2 deficiencyTotal: 1

ZTTK syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005891.3. 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			1 clinvar	3 clinvar	1 clinvar	5
missense			58 clinvar	3 clinvar	1 clinvar	62
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	61	6	2	69

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005891.3	RefSeq	NP_005882.2	9	MANE Select
ENST00000367048.5	Ensembl	ENSP00000356015.4	9	MANE Select
NM_001303253.1	RefSeq	NP_001290182.1	9	Standard
ENST00000869581.1	Ensembl	ENSP00000539640.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mevalonate pathway
Tryptophan metabolism - Homo sapiens (human)
Pyruvate metabolism - Homo sapiens (human)
Butanoate metabolism - Homo sapiens (human)
Fat digestion and absorption - Homo sapiens (human)

Biological Process

lipid metabolic process
fatty acid beta-oxidation
cholesterol biosynthetic process

Molecular Function

acetyl-CoA C-acetyltransferase activity
acetyl-CoA C-acyltransferase activity
protein binding

Cellular Component

nucleus
nucleolus
cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367048
Coding exons: 9
Length: 18785
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.699	190	219	0.867	0.0000104	2561
Missense (PolyPhen)		57	87.792	0.64926		1046
Synonymous	0.418	68	72.5	0.938	0.00000331	817
Loss of Function	1.12	12	17.0	0.706	7.82e-7	218

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.259

Intolerance Scores

LoFtool: 0.537
RVIS EVS: -0.36
RVIS percentile EVS: 28.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.348

Gene Damage Prediction

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