COX4I2

protein-coding

cytochrome c oxidase subunit 4I2, 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 isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]

Previous symbols:

COX4L2

MANE transcript

NM_032609.3

Inheritance

ClinVar variants

U:46B:16

Top phenotype

Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr20:31,637,912-31,645,006

External References & Databases

Ensembl (ENSG00000131055)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX4I2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The *COX4I2* gene encodes an isoform of a subunit of cytochrome *c* oxidase (COX) that is expressed in lung and pancreatic acinar cells. *COX4I2* was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19268275) in two unrelated probands with exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis. While various names have been given to the constellation of features seen in those with *COX4I2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX4I2* 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 one homozygous missense variant seen in both probands. Of note, this variant has a relatively high allele frequency in gnomAD v4.0.0 (allele frequency 0.0003940, including two homozygotes). This Expert Panel elected to include these cases at minimal scoring given that the variant frequency did not seem sufficiently high enough to entirely exclude the variants as causative and the shared phenotype of exocrine pancreatic insufficiency and dyserythropoeitic anemia is unique. The mechanism of disease is loss of function This gene-disease association is also supported by its known biochemical function of *COX4I2* as a subunit of complex IV, functional alteration in non-patient cells (PMID: 32075102), and a knockout mouse model (PMID: 22730437). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 18, 2024 (SOP Version 10).

pancreatic insufficiency-anemia-hyperostosis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012992

Submitter: Orphanet

Clinical Genomic Database (CGD)

Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosisAR

Manifestation: Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic

Intervention: Gastrointestinal

Rationale: Pancreatic enzyme supplementation has been reported to improve psychomotor development, as well as direct sequelae such as steatorrhea

Refs: 19268275

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX4I2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 48

not specifiedTotal: 29

Pancreatic insufficiency-anemia-hyperostosis syndromeTotal: 7

COX4I2-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032609.3. 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	11 clinvar		12
missense			43 clinvar	5 clinvar		48
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	0	0	46	16	0	62

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032609.3	RefSeq	NP_115998.2	4	MANE Select
ENST00000376075.4	Ensembl	ENSP00000365243.3	4	MANE Select
ENST00000890502.1	Ensembl	ENSP00000560561.1	4	Standard
ENST00000890502.2	Ensembl	ENSP00000560561.1	4	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
cellular respiration
oxidation-reduction process
cellular response to hypoxia

Molecular Function

cytochrome-c oxidase activity

Cellular Component

mitochondrial respiratory chain complex IV

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376075
Coding exons: 4
Length: 7119
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 69
Defined: 125747
p: 0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0669	105	103	1.02	0.00000681	1106
Missense (PolyPhen)		42	38.128	1.1016		444
Synonymous	-0.405	41	37.8	1.08	0.00000237	312
Loss of Function	0.824	7	9.78	0.716	5.21e-7	104

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.0014	0.0014	notable
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.000067	0.000065	rare
Other	0.00082	0.00081	rare

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: 0.111

Intolerance Scores

LoFtool: 0.807
RVIS EVS: 0.86
RVIS percentile EVS: 88.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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