CYBA

protein-coding

cytochrome b-245 alpha chain

Gene summary

Cytochrome b is comprised of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), that is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000101.4

Inheritance

ClinVar variants

P:86U:135B:145

Top phenotype

Granulomatous disease, chronic, autosomal recessive, 4

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr16:88,643,275-88,651,083

External References & Databases

Ensembl (ENSG00000051523)

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

granulomatous disease, chronic, autosomal recessive, cytochrome b-negativeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009308

Submitter: Natera

chronic granulomatous diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018305

Submitter: Orphanet

granulomatous disease, chronic, autosomal recessive, cytochrome b-negativeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009308

Submitter: Labcorp Genetics (formerly Invitae)

granulomatous disease, chronic, autosomal recessive, cytochrome b-negativeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009308

Submitter: G2P

Clinical Genomic Database (CGD)

Granulomatous disease, chronic, autosomal recessive, 4AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Surveillance for infections and infectious complications is indicated, and preventive measures (eg, antibacterial/antifungal prophylaxis, interferon gamma) may be beneficial; To treat fungal infections, specific antifungal drugs may be beneficial, and longer treatment courses (as well as specific considerations including coadministration with corticosteroids) may be indicated in individuals with CGD; In some instances, HSCT may be beneficial; Certain agents should be avoided, including material that would allow fungal spore inhalation

Refs: 4384563; 2770793; 3368442; 2713485; 2243141; 1415254; 11060536; 12073015; 18422995; 10759707; 20407811; 22336310; 22562447; 22876374; 22924696; 23910690

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYBA variants in ClinVar

9 Conditions Cataloged

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negativeTotal: 443

Chronic granulomatous diseaseTotal: 111

not providedTotal: 50

not specifiedTotal: 34

Inborn genetic diseasesTotal: 30

CYBA-related disorderTotal: 20

Polyglandular autoimmune syndrome, type 1Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000101.4. 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			3 clinvar	138 clinvar	1 clinvar	142
missense	2 clinvar	13 clinvar	125 clinvar	6 clinvar		146
nonsense	13 clinvar	4 clinvar	1 clinvar			18
start loss		3 clinvar				3
frameshift	15 clinvar	15 clinvar	4 clinvar			34
splice donor/acceptor (+/-2bp)	6 clinvar	15 clinvar	2 clinvar			23
Total	36	50	135	144	1	366

Highest pathogenic variant AF is 0.00006320682

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000101.4	RefSeq	NP_000092.2	6	MANE Select
ENST00000261623.8	Ensembl	ENSP00000261623.3	6	MANE Select
ENST00000565588.6	Ensembl	ENSP00000455537.2	6	Standard
ENST00000566229.1	Ensembl	ENSP00000457060.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics
NOD-like receptor signaling pathway - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
Leishmaniasis - Homo sapiens (human)

Biological Process

response to hypoxia
positive regulation of endothelial cell proliferation
negative regulation of glomerular filtration by angiotensin
superoxide metabolic process
inflammatory response

Molecular Function

protein binding
electron transfer activity
superoxide-generating NADPH oxidase activity
SH3 domain binding
heme binding

Cellular Component

stress fiber
nucleus
endosome
endoplasmic reticulum membrane
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261623
Coding exons: 6
Length: 7870
Individuals with no LoFs: 125594
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125619
p: 0.0000995

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.215	123	130	0.947	0.00000947	1188
Missense (PolyPhen)		56	58.359	0.95958		511
Synonymous	-0.622	66	59.9	1.10	0.00000482	404
Loss of Function	0.206	8	8.65	0.925	3.71e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. Associates with NOX3 to form a functional NADPH oxidase constitutively generating superoxide. {ECO:0000269|PubMed:15824103}.;
Disease: DISEASE: Granulomatous disease, chronic, cytochrome-b-negative, autosomal recessive (ARCGD) [MIM:233690]: A disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections. {ECO:0000269|PubMed:10759707, ECO:0000269|PubMed:10910929, ECO:0000269|PubMed:10914676, ECO:0000269|PubMed:1415254, ECO:0000269|PubMed:1763037, ECO:0000269|PubMed:18422995, ECO:0000269|PubMed:2243141, ECO:0000269|PubMed:23910690, ECO:0000269|PubMed:7964505, ECO:0000269|PubMed:8168815}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.418

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.940

Gene Damage Prediction

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