IL21R
protein-codinginterleukin 21 receptor, the group of CD molecules|Interleukin receptors
Gene summary
The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). It belongs to the type I cytokine receptors, and has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and natural killer (NK) cells. The ligand binding of this receptor leads to the activation of multiple downstream signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Knockout studies of a similar gene in mouse suggest a role for this gene in regulating immunoglobulin production. Three alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~49.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014082
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014082
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014082
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014082
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0021094
Submitter: ClinGen
*IL21R* was first reported in relation to autosomal recessive Immunodeficiency 56 in 2013 (PMID: 23440042). The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). IL21R has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21 with pleiotropic effects on many immune cell types, including promoting CD8+ T cell activation and proliferation, NK cell maturation and cytotoxicity, differentiation of CD4+ T cells, including regulatory T cells, in addition to B cells proliferation, memory B cell formation, isotype switching, and differentiation to plasma cells (PMID: 33929673). This gene-disease relationship is supported by both genetic and experimental evidence. At least eight variants (missense, splice site, deletion, nonsense and frameshift) have been reported in thirteen probands (PMIDs: 23440042, 25769540, 17234735, and 33929673). The main clinical manifestations were recurrent bacterial, fungal, and viral infections; cryptosporidiosis-associated cholangitis; and asthma (PMID: 33929673). The reported biallelic IL21R variants has been shown to result in functional defects in T cells and impaired generation of memory B cells and induction of class switching (PMID: 33929673). A major role of IL21R in immune system regulation has been demonstrated by the sustained Treg defect detected in Il2−/−Il21r−/− double knockout mice (PMID: 24446516). In summary, *IL21R* is definitively associated with autosomal recessive immunodeficiency, 56. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals may manifest with immunodeficiency, and prophylactic measures, as well as early and aggressive treatment of infections may be beneficial; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IL21R variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181078.3. 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 | 5 | 122 | 3 | 130 | ||
| missense | 1 | 202 | 16 | 219 | ||
| nonsense | 2 | 1 | 3 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 3 | 2 | 7 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 6 | 6 | 211 | 138 | 3 | 364 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_851564.1 | 8 | MANE Select | |
| Ensembl | ENSP00000338010.3 | 8 | MANE Select | |
| RefSeq | NP_068570.1 | 8 | Standard | |
| RefSeq | NP_851565.4 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Inflammatory bowel disease (IBD) - Homo sapiens (human)
- Th17 cell differentiation - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- JAK-STAT-Core
Biological Process
- natural killer cell activation
- interleukin-21-mediated signaling pathway
Molecular Function
- interleukin-21 receptor activity
- transmembrane signaling receptor activity
- cytokine receptor activity
Cellular Component
- plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000337929
- Coding exons
- 8
- Length
- 48633
- Individuals with no LoFs
- 125738
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125748
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.749 | 272 | 309 | 0.880 | 0.0000174 | 3455 |
| Missense (PolyPhen) | 48 | 74.311 | 0.64593 | 893 | ||
| Synonymous | 0.924 | 124 | 138 | 0.900 | 0.00000869 | 1105 |
| Loss of Function | 4.26 | 1 | 23.1 | 0.0433 | 9.84e-7 | 269 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000036 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This is a receptor for interleukin-21.;
- Disease
- DISEASE: Immunodeficiency 56 (IMD56) [MIM:615207]: An autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class- switched B-cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens. {ECO:0000269|PubMed:23440042}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Chromosomal aberrations involving IL21R is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;16)(q27;p11), with BCL6.;
Recessive Scores
- pRec
- 0.211
Intolerance Scores
- LoFtool
- 0.168
- RVIS EVS
- 0.64
- RVIS percentile EVS
- 84.05
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |