GeneBe

CYBB

protein-coding

cytochrome b-245 beta chain

Gene summary

Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]

Previous symbols:
  • CGD

MANE transcript

NM_000397.4

Inheritance

XL, AR, XLR

ClinVar variants

P:216U:265B:229

Top phenotype

Granulomatous disease, chronic, X-linked; Immunodeficiency 34

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:37,780,018-37,813,461

External References & Databases

Ensembl (ENSG00000165168)NCBI Gene (1536)OMIM (300481)HGNC:2578GenCCUniProt (P04839)AlphaFoldClinVar (CYBB)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~33.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

granulomatous disease, chronic, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010600

Submitter: Labcorp Genetics (formerly Invitae)

chronic granulomatous diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018305

Submitter: Orphanet

granulomatous disease, chronic, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010600

Submitter: G2P

X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010389

Submitter: Labcorp Genetics (formerly Invitae)

granulomatous disease, chronic, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010600

Submitter: Ambry Genetics

granulomatous disease, chronic, X-linkedDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010600

Submitter: Natera

Clinical Genomic Database (CGD)

Granulomatous disease, chronic, X-linked; Immunodeficiency 34XL

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: In Immunodeficiency 34, BCG vacine should be avoided, and recognition may allow prompt diagnosis and treatment of infectious manifestations; In Chronic granulomatous disease, X-linked, 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: 13430573; 13636694; 14258653; 4163887; 6021213; 4191616; 7273485; 6851217; 3011845; 2556453; 1710153; 8807090; 9454688; 9888386; 10914676; 11060536; 11259721; 11138621; 12802027; 17544093; 18762975; 21278736; 22236433; 22876374; 22924737; 23193493; 23826567; 23827747; 23859418; 23910690Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYBB variants in ClinVar

13 Conditions Cataloged
Granulomatous disease, chronic, X-linkedTotal: 657
not providedTotal: 174
Chronic granulomatous diseaseTotal: 83
not specifiedTotal: 63
Inborn genetic diseasesTotal: 24
CYBB-related disordersTotal: 23
CYBB-related disorderTotal: 20
X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiencyTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000397.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
20
clinvar
174
clinvar
15
clinvar
 211
missense
37
clinvar
32
clinvar
225
clinvar
35
clinvar
5
clinvar
 334
nonsense
39
clinvar
8
clinvar
11
clinvar
 58
start loss
2
clinvar
 2
frameshift
48
clinvar
10
clinvar
1
clinvar
 59
splice donor/acceptor (+/-2bp)
31
clinvar
7
clinvar
8
clinvar
 46
Total1585826520920710

Highest pathogenic variant AF is 0.000008925065

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000397.4RefSeqNP_000388.213MANE Select
ENST00000378588.5EnsemblENSP00000367851.413MANE Select
ENST00000696170.1EnsemblENSP00000512461.15Standard
ENST00000696171.1EnsemblENSP00000512462.112Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cybbDanio rerio

Structure: respiratory burst

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
  • HIF-1 signaling pathway - Homo sapiens (human)
  • Phagosome - Homo sapiens (human)
  • Necroptosis - Homo sapiens (human)
  • NOD-like receptor signaling pathway - Homo sapiens (human)

Biological Process

  • superoxide metabolic process
  • defense response
  • inflammatory response
  • electron transport chain
  • ion transmembrane transport

Molecular Function

  • voltage-gated ion channel activity
  • protein binding
  • electron transfer activity
  • superoxide-generating NADPH oxidase activity
  • heme binding

Cellular Component

  • nuclear envelope
  • endoplasmic reticulum membrane
  • rough endoplasmic reticulum
  • Golgi apparatus
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378588
Coding exons
13
Length
33451
Individuals with no LoFs
125609
Homozygous LoFs
0
Heterozygous LoFs
3
Defined
125612
p
0.0000119
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.191252150.5800.00001613750
Missense (PolyPhen)2677.1260.337111251
Synonymous-0.4828579.51.070.000005881084
Loss of Function4.40124.50.04080.00000196359

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000800.000062rare
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish0.000130.000099rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. It is the terminal component of a respiratory chain that transfers single electrons from cytoplasmic NADPH across the plasma membrane to molecular oxygen on the exterior. Also functions as a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes. It participates in the regulation of cellular pH and is blocked by zinc.;
Disease
DISEASE: Granulomatous disease, chronic, X-linked (CGD) [MIM:306400]: 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:10089913, ECO:0000269|PubMed:10914676, ECO:0000269|PubMed:11462241, ECO:0000269|PubMed:11997083, ECO:0000269|PubMed:12139950, ECO:0000269|PubMed:15338276, ECO:0000269|PubMed:1710153, ECO:0000269|PubMed:18773283, ECO:0000269|PubMed:22125116, ECO:0000269|PubMed:23910690, ECO:0000269|PubMed:2556453, ECO:0000269|PubMed:27666509, ECO:0000269|PubMed:7927345, ECO:0000269|PubMed:8101486, ECO:0000269|PubMed:8182143, ECO:0000269|PubMed:8916969, ECO:0000269|PubMed:9111587, ECO:0000269|PubMed:9585602, ECO:0000269|PubMed:9667376, ECO:0000269|PubMed:9794433, ECO:0000269|PubMed:9856476, ECO:0000269|PubMed:9888386}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 34 (IMD34) [MIM:300645]: A form of Mendelian susceptibility to mycobacterial disease, a rare condition characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. {ECO:0000269|PubMed:21278736}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.749

Intolerance Scores

LoFtool
0.0105
RVIS EVS
0.35
RVIS percentile EVS
74.18

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.307

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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