NOS2

protein-coding

nitric oxide synthase 2

Gene summary

Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

Previous symbols:

NOS2A

MANE transcript

NM_000625.4

Inheritance

—

ClinVar variants

P:1U:146B:42

Top phenotype

NOS2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr17:27,756,766-27,800,529

External References & Databases

Ensembl (ENSG00000007171)

Transcript & Mutation Effects

hg38 • Region Span ~43.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NOS2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 153

not providedTotal: 33

NOS2-related disorderTotal: 9

Primary ciliary dyskinesiaTotal: 1

Malaria, susceptibility toTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000625.4. 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				20 clinvar	5 clinvar	25
missense			144 clinvar	17 clinvar		161
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	0	1	146	37	5	189

Highest pathogenic variant AF is 0.0000024787018

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000625.4	RefSeq	NP_000616.3	26	MANE Select
ENST00000313735.11	Ensembl	ENSP00000327251.6	26	MANE Select
ENST00000646938.1	Ensembl	ENSP00000494870.1	26	Standard
ENST00000646938.2	Ensembl	ENSP00000494870.1	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Relaxin signaling pathway - Homo sapiens (human)
Arginine and proline metabolism - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)

Biological Process

response to hypoxia
positive regulation of leukocyte mediated cytotoxicity
innate immune response in mucosa
arginine catabolic process
protein targeting to peroxisome

Molecular Function

NADPH-hemoprotein reductase activity
nitric-oxide synthase activity
signaling receptor binding
protein binding
calmodulin binding

Cellular Component

nucleus
cytoplasm
peroxisome
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313735
Coding exons: 26
Length: 43734
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.78	534	663	0.805	0.0000398	7523
Missense (PolyPhen)		171	266.89	0.64071		3084
Synonymous	0.989	253	274	0.924	0.0000173	2217
Loss of Function	3.08	33	58.4	0.565	0.00000282	673

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00044	0.00043	rare
South Asian	0.00040	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body (PubMed:7531687, PubMed:7544004). In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such PTGS2/COX2 (By similarity). As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys-247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM (PubMed:25417112). Involved in inflammation, enhances the synthesis of proinflammatory mediators such as IL6 and IL8 (PubMed:19688109). {ECO:0000250|UniProtKB:P29477, ECO:0000269|PubMed:19688109, ECO:0000269|PubMed:25417112, ECO:0000269|PubMed:7531687, ECO:0000269|PubMed:7544004}.;

Recessive Scores

pRec: 0.950

Intolerance Scores

LoFtool: 0.549
RVIS EVS: -1.68
RVIS percentile EVS: 2.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.968

Gene Damage Prediction

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