IL2RG
protein-codinginterleukin 2 receptor subunit gamma, the group of CD molecules|Interleukin receptors|Fibronectin type III domain containing
Gene summary
The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]
- SCIDX1
- IMD4
- CIDX
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010315
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011338
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010315
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010315
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010315
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010315
Submitter: ClinGen
IL2RG was first reported in relation to X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency in 1993 (Puck et al. PMID:8401490). T-B+ severe combined immunodeficiency due to gamma chain deficiency is a form of SCID characterized by severe and recurrent infections, associated with diarrhea and failure to thrive. This disease differs from the Bruton type of agammaglobulinemia by the additional presence of lymphocytopenia, earlier age at death, vulnerability to viral and fungal as well as bacterial infections, lack of delayed hypersensitivity, atrophy of the thymus, and lack of benefit from gamma globulin administration. X-linked combined immunodeficiency is a less severe form of the disorder that is also caused by mutation in the IL2RG gene. At least 11 unique variants (missense, nonsense, splice donor) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. IL2RG has been noted to be associated with the following disease entities: Combined immunodeficiency, X-linked (moderate) and Severe combined immunodeficiency, X-linked. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, or inheritance pattern or phenotypic variability. Therefore, the two disease assertions have been lumped into one disease entity: T-B+ severe combined immunodeficiency due to gamma chain deficiency (MONDO:0010315). Summary of Case Level Data – 11.3 POINTS: Variants in this gene have been reported in at least 14 probands in 7 publications (PMID: 7883965, PMID: 9399950, PMID: 8317482, PMID: 8462096, PMID: 7632950, PMID: 23790094, PMID: 9058718). T-B+ severe combined immunodeficiency due to gamma chain deficiency is caused by a hemizygous pathogenic variant in IL2RG. In typical X-SCID, lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. This gene-disease association is supported by animal models, functional alteration studies, and protein interaction studies (PMID: 7632950, PMID: 7697543, PMID: 29606506, PMID: 8266078, PMID: 7973659). IL2RG is the gamma subunit of the interleukin-2 receptor. Stimulation with IL-2 induces the tyrosine phosphorylation and activation of the Janus kinases Jak1 and Jak3. IL2RG is also a functional component of the IL-4 receptor and associates with the IL-7 receptor. Cao et al. (1995) showed defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Experimental evidence demonstrates why deficiency of this common gamma chain has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency. In summary, there is definitive evidence to support the relationship between IL2RG and X-linked, T-B+ severe combined immunodeficiency due to gamma chain deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date March 18, 2021 (SOP Version 8).
Inheritance Pattern: XL
Disease ID:MONDO:0010315
Submitter: Myriad Women's Health
Inheritance Pattern: XLR
Disease ID:MONDO:0010315
Submitter: Natera
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections is indicated prior to attempts at immune reconstitution; Chronic immunoglobulin therapy may be required even after treatment aimed at immune reconstitution, which is necessary for survival; BMT/HSCT has been described, as has the use of gene therapy in individuals who are not candidates for or who have failed BMT
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IL2RG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000206.3. 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 | 1 | 10 | 91 | 8 | 111 |
| missense | 19 | 36 | 134 | 29 | 6 | 224 |
| nonsense | 31 | 8 | 5 | 44 | ||
| start loss | 1 | 1 | ||||
| frameshift | 39 | 10 | 4 | 53 | ||
| splice donor/acceptor (+/-2bp) | 17 | 4 | 9 | 30 | ||
| Total | 108 | 59 | 162 | 120 | 14 | 463 |
Highest pathogenic variant AF is 0.000013253119
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000197.1 | 8 | MANE Select | |
| Ensembl | ENSP00000363318.3 | 8 | MANE Select | |
| RefSeq | NP_001425799.1 | 6 | Standard | |
| Ensembl | ENSP00000425233.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| il2rga | Danio rerio | Structure: mature B cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Primary immunodeficiency - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Inflammatory bowel disease (IBD) - Homo sapiens (human)
Biological Process
- MAPK cascade
- immune response
- signal transduction
- viral process
- cytokine-mediated signaling pathway
Molecular Function
- cytokine receptor activity
- interleukin-2 receptor activity
- interleukin-4 receptor activity
- interleukin-7 receptor activity
- Ras guanyl-nucleotide exchange factor activity
Cellular Component
- endosome
- cytosol
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374202
- Coding exons
- 8
- Length
- 4705
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.49 | 86 | 135 | 0.639 | 0.0000102 | 2416 |
| Missense (PolyPhen) | 14 | 39.318 | 0.35607 | 731 | ||
| Synonymous | 0.0665 | 53 | 53.6 | 0.988 | 0.00000393 | 700 |
| Loss of Function | 3.50 | 0 | 14.3 | 0.00 | 0.00000106 | 221 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Common subunit for the receptors for a variety of interleukins.;
- Disease
- DISEASE: Severe combined immunodeficiency X-linked T-cell- negative/B-cell-positive/NK-cell-negative (XSCID) [MIM:300400]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:7557965, ECO:0000269|PubMed:7668284, ECO:0000269|PubMed:7860773, ECO:0000269|PubMed:7937790, ECO:0000269|PubMed:8027558, ECO:0000269|PubMed:8088810, ECO:0000269|PubMed:8299698, ECO:0000269|PubMed:8401490, ECO:0000269|PubMed:8900089, ECO:0000269|PubMed:9049783, ECO:0000269|PubMed:9150740}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: X-linked combined immunodeficiency (XCID) [MIM:312863]: Less severe form of X-linked immunodeficiency with a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID. {ECO:0000269|PubMed:7883965, ECO:0000269|PubMed:9399950}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.554
Intolerance Scores
- LoFtool
- 0.119
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 36.86
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.927
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |