IL6R
protein-codinginterleukin 6 receptor, the group of CD molecules|Interleukin receptors|Immunoglobulin like domain containing
Gene summary
This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9. [provided by RefSeq, Aug 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~64.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030069
Submitter: ClinGen
IL6R was first reported in relation to an autosomal recessive hyper-IgE recurrent infection syndrome 5, in 2019 (Spencer S, et al., 2019, PMID: 31235509). This disease is characterized by onset of recurrent sinopulmonary and deep skin infections in early childhood. Infections are mostly bacterial and patient’s infections usually lack erythema, pyrexia and C-reactive protein (CRP) was absent or at very low levels. All patients presented extremely high levels of IgE, while other immunoglobulins have normal or near normal levels. All cases reported were homozygous for nonsense mutations. The curation of IL6R related to autosomal recessive hyper-IgE recurrent infection syndrome 5 with MONDO ID 0030069 includes both case-level and experimental Six cases in total were found with different missense and nonsense mutations (PMIDs: 31235509, 31778705). A score of 3.2 points for genetic evidence has been reached. This gene-disease association is also supported by expression and rescue models (PMID: 31778705). Minimal IL6R expression was observed on patients’ cells, as was a notable reduction in expression by heterozygous parental cells compared with those from healthy control subjects. Lack of IL6-induced STAT3 activation in patients' EBV B-cell lines was rescued by incubating patients’ EBV B-cells with recombinant soluble IL6R (sIL6R) complexed with IL6. A score of 1.5 points for experimental evidence has been reached, increasing the total score to 4.7 points. In summary, IL6R has a limited association with autosomal recessive hyper-IgE recurrent infection syndrome 5. More cases and research will be needed to elevate the classification. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date September 21, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0030069
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0030069
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030069
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: The condition can involve early-onset recurrent and sever inffections, and awareness may allow prophylaxis and early and aggressive treatment of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IL6R variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000565.4. 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 | 3 | 95 | 6 | 104 | ||
| missense | 1 | 130 | 7 | 138 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 1 | 0 | 141 | 102 | 6 | 250 |
Highest pathogenic variant AF is 0.0000065715976
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000556.1 | 10 | MANE Select | |
| Ensembl | ENSP00000357470.3 | 10 | MANE Select | |
| RefSeq | NP_001193795.1 | 7 | Standard | |
| RefSeq | NP_001369698.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
- HIF-1 signaling pathway - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Th17 cell differentiation - Homo sapiens (human)
Biological Process
- hepatic immune response
- monocyte chemotaxis
- positive regulation of leukocyte chemotaxis
- positive regulation of T-helper 1 type immune response
- acute-phase response
Molecular Function
- cytokine receptor activity
- ciliary neurotrophic factor receptor activity
- interleukin-6 receptor activity
- interleukin-6 receptor binding
- interleukin-12 receptor binding
Cellular Component
- extracellular region
- plasma membrane
- interleukin-6 receptor complex
- external side of plasma membrane
- basolateral plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000368485
- Coding exons
- 10
- Length
- 64258
- Individuals with no LoFs
- 125708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 39
- Defined
- 125747
- p
- 0.000155
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.689 | 254 | 287 | 0.885 | 0.0000173 | 3017 |
| Missense (PolyPhen) | 51 | 72.546 | 0.703 | 813 | ||
| Synonymous | -0.196 | 128 | 125 | 1.02 | 0.00000849 | 971 |
| Loss of Function | 2.23 | 11 | 22.4 | 0.491 | 0.00000102 | 245 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.;
Recessive Scores
- pRec
- 0.707
Intolerance Scores
- LoFtool
- 0.530
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 42.16
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.985
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |