ACO2

aconitase 2

Basic information

Region (hg38): 22:41447829-41529273

Links

ENSG00000100412 ∙ NCBI:50 ∙ OMIM:100850 ∙ HGNC:118 ∙ Uniprot:Q99798 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• infantile cerebellar-retinal degeneration (Strong), mode of inheritance: AR
• autosomal recessive optic atrophy (Supportive), mode of inheritance: AR
• infantile cerebellar-retinal degeneration (Supportive), mode of inheritance: AR
• optic atrophy 9 (Moderate), mode of inheritance: AD
• optic atrophy 9 (Strong), mode of inheritance: AR
• infantile cerebellar-retinal degeneration (Strong), mode of inheritance: AR
• optic atrophy 9 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Infantile cerebellar-retinal degeneration; Optic atrophy 9	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Audiologic/Otolaryngologic; Neurologic; Ophthalmologic	22405087; 25351951; 31106992

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACO2 gene.

• not provided (610 variants)
• not specified (35 variants)
• Infantile cerebellar-retinal degeneration (29 variants)
• Optic atrophy 9 (21 variants)
• Inborn genetic diseases (21 variants)
• Infantile cerebellar-retinal degeneration;Optic atrophy 9 (5 variants)
• OPTIC ATROPHY 9, AUTOSOMAL RECESSIVE (4 variants)
• Central hypoventilation;Neurodegeneration;Global developmental delay;Brain atrophy;Progressive microcephaly (3 variants)
• Optic atrophy 9;Infantile cerebellar-retinal degeneration (2 variants)
• ACO2-related condition (2 variants)
• Neurodegeneration;Global developmental delay;Central hypoventilation;Brain atrophy;Progressive microcephaly (1 variants)
• Isolated macular dystrophy (1 variants)
• Mitochondrial disease (1 variants)
• Acute intermittent porphyria (1 variants)
• ACO2-related disorders (1 variants)
• ACO2-related disorder (1 variants)
• Retinal dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACO2 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			11	137	6	154
missense	1	4	234	1	1	241
nonsense	14	1				15
start loss						0
frameshift	16	6				22
inframe indel			13			13
splice donor/acceptor (+/-2bp)	1	8	1			10
splice region		1	13	16	1	31
non coding			7	111	27	145
Total	32	19	266	249	34

Highest pathogenic variant AF is 0.0000263

Variants in ACO2

This is a list of pathogenic ClinVar variants found in the ACO2 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-41467579-GCA-G			Uncertain significance (Sep 20, 2023)
22-41467614-C-A			Uncertain significance (Apr 01, 2022)
22-41468643-T-C			Uncertain significance (Aug 14, 2019)
22-41469029-G-C			Likely benign (Jun 16, 2018)
22-41469151-C-T			Uncertain significance (Sep 15, 2022)
22-41469153-C-T			Uncertain significance (May 01, 2023)
22-41469155-C-T			Likely benign (Dec 28, 2018)
22-41469162-C-T			Likely benign (Jan 10, 2024)
22-41469165-C-G			Uncertain significance (Jul 17, 2023)
22-41469167-G-A			Likely benign (Sep 16, 2021)
22-41469172-C-T			Uncertain significance (Jan 02, 2024)
22-41469177-C-T			Likely benign (Nov 10, 2023)
22-41469180-C-T			Pathogenic (Oct 12, 2015)
22-41469182-G-A		Optic atrophy 9	Likely pathogenic (Jun 28, 2023)
22-41469184-T-A			Likely pathogenic (Aug 23, 2022)
22-41469185-G-A			Uncertain significance (Mar 09, 2022)
22-41469189-G-C			Likely benign (Dec 19, 2021)
22-41469194-C-G			Likely benign (Sep 20, 2023)
22-41469195-A-G			Likely benign (Jun 15, 2022)
22-41469200-C-A			Likely benign (Mar 10, 2022)
22-41469200-C-T			Likely benign (Nov 08, 2022)
22-41469202-T-C			Likely benign (Apr 17, 2022)
22-41469330-G-A			Benign (Jun 28, 2018)
22-41499405-G-A			Benign (Jun 26, 2018)
22-41499741-C-T			Uncertain significance (Dec 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACO2	protein_coding	protein_coding	ENST00000216254	18	59865

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.208	0.792	125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.92	304	485	0.627	0.0000297	5107
Missense in Polyphen		122	242.15	0.50382		2551
Synonymous	0.0883	201	203	0.992	0.0000136	1584
Loss of Function	4.33	9	37.7	0.239	0.00000187	426

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000579	0.0000579
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000802	0.0000791
Middle Eastern	0.000109	0.000109
South Asian	0.000198	0.000196
Other	0.000165	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the isomerization of citrate to isocitrate via cis-aconitate. {ECO:0000250|UniProtKB:P16276}.
• Disease: DISEASE: Infantile cerebellar-retinal degeneration (ICRD) [MIM:614559]: A severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration. {ECO:0000269|PubMed:22405087, ECO:0000269|PubMed:25351951}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Optic atrophy 9 (OPA9) [MIM:616289]: A condition that features progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. {ECO:0000269|PubMed:25351951}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Citrate cycle (TCA cycle) - Homo sapiens (human);Glyoxylate and dicarboxylate metabolism - Homo sapiens (human);Warburg Effect;The oncogenic action of Succinate;The oncogenic action of Fumarate;Pyruvate dehydrogenase deficiency (E3);Pyruvate dehydrogenase deficiency (E2);2-ketoglutarate dehydrogenase complex deficiency;Mitochondrial complex II deficiency;Fumarase deficiency;Congenital lactic acidosis;Citric Acid Cycle;Glutaminolysis and Cancer;The oncogenic action of 2-hydroxyglutarate;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;fig-met-1-last-solution;Amino Acid metabolism;TCA Cycle;Citrate cycle;Citric acid cycle (TCA cycle);Pyruvate metabolism and Citric Acid (TCA) cycle;Metabolism of proteins;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;TCA cycle;TCA cycle;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;Mitochondrial protein import (Consensus)

Recessive Scores

• pRec: 0.782

Intolerance Scores

• loftool: 0.428
• rvis_EVS: -1
• rvis_percentile_EVS: 8.47

Haploinsufficiency Scores

• pHI: 0.461
• hipred: Y
• hipred_score: 0.651
• ghis: 0.572

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.987

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Aco2

Gene ontology

• Biological process: liver development;generation of precursor metabolites and energy;tricarboxylic acid cycle;citrate metabolic process;isocitrate metabolic process;response to isolation stress
• Cellular component: mitochondrion;mitochondrial matrix;cytosol;myelin sheath
• Molecular function: aconitate hydratase activity;iron ion binding;3 iron, 4 sulfur cluster binding;4 iron, 4 sulfur cluster binding