NCF2

protein-coding

neutrophil cytosolic factor 2, the group of Tetratricopeptide repeat domain containing

Gene summary

This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

MANE transcript

NM_000433.4

Inheritance

ClinVar variants

P:78U:195B:171

Top phenotype

Granulomatous disease, chronic, autosomal recessive, 2

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr1:183,554,461-183,590,905

External References & Databases

Ensembl (ENSG00000116701)

Transcript & Mutation Effects

hg38 • Region Span ~36.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009310

Submitter: PanelApp Australia

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009310

Submitter: Labcorp Genetics (formerly Invitae)

chronic granulomatous diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018305

Submitter: Orphanet

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009310

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Granulomatous disease, chronic, autosomal recessive, 2AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Surveillance for infections and infectious complications is indicatred, 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: 2770793; 7795241; 10498624; 11060536; 22157170; 22876374; 23264412

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NCF2 variants in ClinVar

7 Conditions Cataloged

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2Total: 570

not providedTotal: 82

not specifiedTotal: 53

Inborn genetic diseasesTotal: 44

NCF2-related disorderTotal: 23

Chronic granulomatous diseaseTotal: 10

Developmental and epileptic encephalopathy, 28Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000433.4. 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	3 clinvar	151 clinvar		155
missense		6 clinvar	180 clinvar	16 clinvar	3 clinvar	205
nonsense	15 clinvar	8 clinvar				23
start loss	1 clinvar	1 clinvar				2
frameshift	17 clinvar	10 clinvar	5 clinvar			32
splice donor/acceptor (+/-2bp)	5 clinvar	14 clinvar	7 clinvar	1 clinvar		27
Total	38	40	195	168	3	444

Highest pathogenic variant AF is 0.000024784253

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000433.4	RefSeq	NP_000424.2	15	MANE Select
ENST00000367535.8	Ensembl	ENSP00000356505.4	15	MANE Select
NM_001127651.3	RefSeq	NP_001121123.1	15	Standard
NM_001190789.2	RefSeq	NP_001177718.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
Leishmaniasis - Homo sapiens (human)
Osteoclast differentiation - Homo sapiens (human)
Leukocyte transendothelial migration - Homo sapiens (human)

Biological Process

superoxide metabolic process
phagocytosis
cellular defense response
electron transport chain
superoxide anion generation

Molecular Function

protein binding
protein C-terminus binding
electron transfer activity
superoxide-generating NADPH oxidase activity
superoxide-generating NADPH oxidase activator activity

Cellular Component

acrosomal vesicle
nucleolus
cytosol
phagolysosome
NADPH oxidase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367535
Coding exons: 15
Length: 35314
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.04	225	273	0.823	0.0000149	3457
Missense (PolyPhen)		73	91.443	0.79831		1141
Synonymous	-0.0865	107	106	1.01	0.00000585	973
Loss of Function	2.71	16	32.7	0.489	0.00000177	380

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00078	0.00078	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production). {ECO:0000269|PubMed:12207919}.;
Disease: DISEASE: Granulomatous disease, chronic, cytochrome-b-positive 2, autosomal recessive (CGD2) [MIM:233710]: 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:10498624, ECO:0000269|PubMed:10598813, ECO:0000269|PubMed:11112388, ECO:0000269|PubMed:16937026, ECO:0000269|PubMed:18625437, ECO:0000269|PubMed:19624736, ECO:0000269|PubMed:20167518, ECO:0000269|PubMed:23910690, ECO:0000269|PubMed:8286749, ECO:0000269|PubMed:9070911}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.324

Intolerance Scores

LoFtool: 0.912
RVIS EVS: 1.31
RVIS percentile EVS: 94.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.590

Gene Damage Prediction

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