COX6A2

protein-coding

cytochrome c oxidase subunit 6A2, the group of Mitochondrial complex IV: cytochrome c oxidase subunits

Gene summary

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes polypeptide 2 (heart/muscle isoform) of subunit VIa, and polypeptide 2 is present only in striated muscles. Polypeptide 1 (liver isoform) of subunit VIa is encoded by a different gene, and is found in all non-muscle tissues. These two polypeptides share 66% amino acid sequence identity. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005205.4

Inheritance

ClinVar variants

P:2U:24B:2

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 18

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr16:31,427,731-31,428,360

External References & Databases

Ensembl (ENSG00000156885)

Transcript & Mutation Effects

hg38 • Region Span ~0.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cytochrome-c oxidase deficiency diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX6A2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The *COX6A2* gene encodes an isoform of a subunit of cytochrome *c* oxidase (COX) that is expressed in skeletal muscle and heart. The first and only report of variants in *COX6A2* in relation to autosomal recessive primary mitochondrial disease was in 2019 (PMID: 31155743), in two probands with congenital myopathy and cardiomyopathy. Complex IV staining was uniformly weak on muscle histology and complex IV deficiency was seen on respiratory chain analyses in muscle and fibroblasts. While various names have been given to the constellation of features seen in those with *COX6A2*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX6A2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two missense variants (PMID: 31155743). The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of COX6A2 as a subunit of complex IV and several *COX6A2* knockout mouse model studies showing similar biochemical phenotypes to those seen in affected individuals (PMIDs: 31155743, 11788423, 23460811). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 18, 2024 (SOP Version 10).

mitochondrial complex IV deficiency, nuclear type 18LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033653

Submitter: Ambry Genetics

mitochondrial complex IV deficiency, nuclear type 18LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033653

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 18AR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Musculoskeletal

Intervention: General

Rationale: 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

Refs: 31155743

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX6A2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 23

not providedTotal: 3

COX6A2-related disorderTotal: 2

Mitochondrial complex IV deficiency, nuclear type 18Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005205.4. 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				1 clinvar		1
missense		2 clinvar	23 clinvar	1 clinvar		26
nonsense						0
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	2	24	2	0	28

Highest pathogenic variant AF is 0.000028796978

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005205.4	RefSeq	NP_005196.1	3	MANE Select
ENST00000287490.5	Ensembl	ENSP00000287490.4	3	MANE Select
ENST00000943485.1	Ensembl	ENSP00000613544.1	3	Standard
ENST00000943485.2	Ensembl	ENSP00000613544.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

generation of precursor metabolites and energy
mitochondrial electron transport, cytochrome c to oxygen
aerobic respiration
regulation of catalytic activity
proton transmembrane transport

Molecular Function

cytochrome-c oxidase activity
enzyme regulator activity

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000287490
Coding exons: 3
Length: 916
Individuals with no LoFs: 108120
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 108121
p: 0.00000462

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.235	41	45.5	0.902	0.00000276	577
Missense (PolyPhen)		20	21.582	0.9267		280
Synonymous	0.353	19	21.1	0.902	0.00000143	206
Loss of Function	0.928	1	2.62	0.382	1.11e-7	40

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000032	0.000032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein is one of the nuclear-coded polypeptide chains of cytochrome c oxidase, the terminal oxidase in mitochondrial electron transport.;

Recessive Scores

pRec: 0.125

Intolerance Scores

LoFtool: 0.296
RVIS EVS: 0.26
RVIS percentile EVS: 69.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.438

Gene Damage Prediction

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