IL1RN

protein-coding

interleukin 1 receptor antagonist, the group of Interleukins

Gene summary

The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses, particularly in the acute phase of infection and inflammation. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

MANE transcript

NM_173842.3

Inheritance

ClinVar variants

P:8U:69B:54

Top phenotype

Chronic recurrent multifocal osteomyelitis 2, with periostitis and pustulosis

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr2:113,099,315-113,134,016

External References & Databases

Ensembl (ENSG00000136689)

Transcript & Mutation Effects

hg38 • Region Span ~34.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sterile multifocal osteomyelitis with periostitis and pustulosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013021

Submitter: Genomics England PanelApp

sterile multifocal osteomyelitis with periostitis and pustulosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013021

Submitter: Orphanet

sterile multifocal osteomyelitis with periostitis and pustulosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013021

Submitter: PanelApp Australia

sterile multifocal osteomyelitis with periostitis and pustulosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013021

Submitter: Labcorp Genetics (formerly Invitae)

sterile multifocal osteomyelitis with periostitis and pustulosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013021

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Chronic recurrent multifocal osteomyelitis 2, with periostitis and pustulosisAR

Manifestation: Allergy/Immunology/Infectious; Dermatologic

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may present in infancy with manifestations including rash, pain, and oral lesions, which may advance to more severe findings such as progressive skin lesions, vasculitis, skeletal lesions, pulmonary disease, and severe inflammatory response syndrome, and medical treatment (eg, with anakinra) has been described as effective

Refs: 19494218; 19494219

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL1RN variants in ClinVar

11 Conditions Cataloged

Sterile multifocal osteomyelitis with periostitis and pustulosisTotal: 130

not providedTotal: 26

not specifiedTotal: 24

Inborn genetic diseasesTotal: 24

Autoinflammatory syndromeTotal: 16

Microvascular complications of diabetes, susceptibility to, 4Total: 6

Gastric cancerTotal: 5

IL1RN-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173842.3. 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	2 clinvar	48 clinvar		51
missense			64 clinvar	5 clinvar	1 clinvar	70
nonsense	3 clinvar	1 clinvar				4
start loss						0
frameshift		3 clinvar	3 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	3	5	69	53	1	131

Highest pathogenic variant AF is 0.000017966491

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173842.3	RefSeq	NP_776214.1	4	MANE Select
ENST00000409930.4	Ensembl	ENSP00000387173.3	4	MANE Select
NM_000577.5	RefSeq	NP_000568.1	5	Standard
NM_001318914.2	RefSeq	NP_001305843.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Leptin signaling pathway
JAK-STAT
Interleukin-10 signaling
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
Signaling by Interleukins

Biological Process

lipid metabolic process
inflammatory response
immune response
regulation of signaling receptor activity
cytokine-mediated signaling pathway

Molecular Function

cytokine activity
interleukin-1 receptor binding
interleukin-1, type I receptor binding
interleukin-1, type II receptor binding
interleukin-1 receptor antagonist activity

Cellular Component

extracellular space
cytoplasm
plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259206
Coding exons: 6
Length: 26803
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00812	100	100	0.998	0.00000561	1187
Missense (PolyPhen)		28	34.166	0.81952		438
Synonymous	-0.797	43	36.8	1.17	0.00000235	326
Loss of Function	1.78	4	10.1	0.397	5.15e-7	122

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibits the activity of interleukin-1 by binding to receptor IL1R1 and preventing its association with the coreceptor IL1RAP for signaling. Has no interleukin-1 like activity. Binds functional interleukin-1 receptor IL1R1 with greater affinity than decoy receptor IL1R2; however, the physiological relevance of the latter association is unsure. {ECO:0000269|PubMed:7775431}.;
Disease: DISEASE: Interleukin 1 receptor antagonist deficiency (DIRA) [MIM:612852]: A rare autoinflammatory disease of skin and bone resulting in sterile multifocal osteomyelitis, periostitis, and pustulosis from birth. The term autoinflammatory disease describes a group of disorders characterized by attacks of seemingly unprovoked inflammation without significant levels of autoantibodies and autoreactive T-cells. {ECO:0000269|PubMed:19494218}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.711

Intolerance Scores

LoFtool: 0.375
RVIS EVS: -0.69
RVIS percentile EVS: 14.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.838

Gene Damage Prediction

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