COQ8B

protein-coding

coenzyme Q8B

Gene summary

This gene encodes a protein with two copies of a domain found in protein kinases. The encoded protein has a complete protein kinase catalytic domain, and a truncated domain that contains only the active and binding sites of the protein kinase domain, however, it is not known whether the protein has any kinase activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

Previous symbols:

ADCK4

MANE transcript

NM_024876.4

Inheritance

AD, AR

ClinVar variants

P:47U:103B:82

Top phenotype

Nephrotic syndrome, type 9

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr19:40,691,514-40,725,784

External References & Databases

Ensembl (ENSG00000123815)

Transcript & Mutation Effects

hg38 • Region Span ~34.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COQ8B* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 6, 2023. The *COQ8B* gene encodes the COQ8B protein, which is an atypical kinase that is expressed in the podocytes of the kidney and localizes to the mitochondrial matrix, where it participates in coenzyme Q10 synthesis. Of note, this gene was previously known as *ADCK4*. The *COQ8B* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 24270420). While various names have been given to the constellation of features seen in those with *COQ8B*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COQ8B* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *COQ8B* and primary mitochondrial disease includes case-level data and experimental data. This curation includes eleven variants (five missense, two nonsense, three frameshift, and one in frame insertion) in eight probands in one publication (PMIDs: 24270420) although additional cases have been reported in the medical literature. Affected individuals typically experience early-onset severe kidney dysfunction (steroid-resistant nephrotic syndrome, or SRNS, that typically leads to end-stage kidney disease) although later onset has also been reported. Treatment with high dose Coenzyme Q10 supplementation early in the course of disease can be beneficial. Other features have been reported including seizures, intellectual disability, hypothyroidism, and retinitis pigmentosa. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function, a mouse model, a zebrafish model, and in vitro functional assays demonstrating oxidative phosphorylation deficiencies due to variants in *COQ8B* (PMIDs: 32381600, 24270420). In summary, there is definitive evidence to support the relationship between *COQ8B* and autosomal recessive primary mitochondrial disease. More than three years have elapsed since the first assertion of this gene-disease relationship, and no contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 6, 2023 (SOP Version 9).

nephrotic syndrome, type 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014257

Submitter: Ambry Genetics

nephrotic syndrome, type 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014257

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Nephrotic syndrome, type 9AR

Manifestation: Renal

Intervention: Biochemical; Renal

Rationale: The condition manifests as steroid-resistant nephrotic syndrome, with focal segmental glomerulosclerosis, and treatment with coenzyme Q10 has been described as beneficial

Refs: 24270420

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COQ8B variants in ClinVar

14 Conditions Cataloged

not providedTotal: 266

Nephrotic syndrome, type 9Total: 53

not specifiedTotal: 37

COQ8B-related disorderTotal: 19

Inborn genetic diseasesTotal: 11

Retinitis pigmentosaTotal: 5

ADCK4 & COQ8B-related disordersTotal: 4

Kidney disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024876.4. 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			2 clinvar	66 clinvar		68
missense	4 clinvar	13 clinvar	94 clinvar	15 clinvar	1 clinvar	127
nonsense	5 clinvar	5 clinvar	1 clinvar			11
start loss						0
frameshift	4 clinvar	5 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	5 clinvar	6 clinvar	5 clinvar			16
Total	18	29	103	81	1	232

Highest pathogenic variant AF is 0.00017038308

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 104 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024876.4	RefSeq	NP_079152.3	14	MANE Select
ENST00000324464.8	Ensembl	ENSP00000315118.3	14	MANE Select
NM_001142555.3	RefSeq	NP_001136027.1	13	Standard
ENST00000243583.10	Ensembl	ENSP00000243583.5	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
coq8b	Danio rerio	Structure: podocyte Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

coq8b

Danio rerio

Structure: podocyte

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
ubiquinone biosynthetic process
cerebellar Purkinje cell layer morphogenesis

Molecular Function

protein kinase activity
ATP binding
kinase activity

Cellular Component

mitochondrion
cytosol
plasma membrane
integral component of membrane
extrinsic component of mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324464
Coding exons: 14
Length: 26679
Individuals with no LoFs: 125656
Homozygous LoFs: 0
Heterozygous LoFs: 92
Defined: 125748
p: 0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.890	303	350	0.866	0.0000225	3473
Missense (PolyPhen)		113	139.3	0.81119		1339
Synonymous	1.68	112	137	0.817	0.00000818	1123
Loss of Function	1.09	23	29.4	0.782	0.00000148	302

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.000098	0.000092	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00057	0.00056	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration (PubMed:24270420). Its substrate specificity is unclear: does not show any protein kinase activity. Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway. Required for podocyte migration (PubMed:24270420). {ECO:0000250|UniProtKB:Q8NI60, ECO:0000269|PubMed:24270420}.;
Disease: DISEASE: Nephrotic syndrome 9 (NPHS9) [MIM:615573]: A form of nephrotic syndrome, a renal disease clinically characterized by progressive renal failure, severe proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show focal segmental glomerulosclerosis. {ECO:0000269|PubMed:24270420, ECO:0000269|PubMed:25967120}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0981

Intolerance Scores

RVIS EVS: 0.03
RVIS percentile EVS: 55.79

Essentials

Essential (gene trap): N