CSF2RB
protein-codingcolony stimulating factor 2 receptor subunit beta, the group of CD molecules|Fibronectin type III domain containing
Gene summary
The protein encoded by this gene is the common beta chain of the high affinity receptor for IL-3, IL-5 and CSF. Defects in this gene have been reported to be associated with protein alveolar proteinosis (PAP). [provided by RefSeq, Jul 2008]
- IL3RB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013712
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013712
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013712
Submitter: ClinGen
*CSF2RB* was first reported in relation to autosomal recessive *CSF2RB*-related alveolar proteinosis in 2011 (Tanaka T, et al., PMID: 21075760). *CSF2RB* encodes the beta subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) cell surface receptor and is involved in signaling pathways that are essential for surfactant clearance. Deficiency of *CSF2RB* results in alveolar macrophage dysfunction, which leads to impaired clearance and accumulation of surfactant in the alveoli and terminal bronchioles. This accumulation results in *CSF2RB*-related surfactant metabolism dysfunction, or pulmonary alveolar proteinosis, with various characteristics including ground-glass opacities with interlobular or intralobular septal thickening, resulting in a “crazy-paving” pattern on radiograph, enlarged foamy alveolar macrophages, dyspnea, and respiratory failure (Tanaka T, et al., PMID: 21075760). The age of onset for those presenting with isolated interstitial lung disease ranges from childhood to adulthood. Four variants (2 frameshift, 1 nonsense, and 1 missense) that have been reported in 4 probands across 4 publications (PMIDs: 21075760, 21205713, 38259275, 38111540) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression studies showing reduced or absent expression of beta chain (*CSF2RB*) in patients with PAP (PMID: 9410898), biochemical function assays demonstrating the role of signaling pathways in surfactant clearance (PMID: 21075760), animal models that recapitulate the human phenotype and a rescue of that phenotype with pulmonary macrophage transplantation (PMID: 25274301). In summary, there is definitive evidence supporting the relationship between *CSF2RB* and autosomal recessive *CSF2RB*-related surfactant metabolism dysfunction. 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 Interstitial Lung Diseases GCEP on the meeting date September 17, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0012580
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Pulmonary
Intervention: Pulmonary
Rationale: The condition typically manifests with childhood-onset respiratory insufficiency (though adult-onset disease has also been reported) due to pulmonary alveolar proteinosis, and whole-lung lavage may be beneficial; It has been reported that diagnosis has important therapeutic implications, as BMT/HSCT can be effective
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CSF2RB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000395.3. 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 | 9 | 215 | 3 | 227 | ||
| missense | 441 | 30 | 1 | 472 | ||
| nonsense | 1 | 6 | 7 | |||
| start loss | 2 | 2 | ||||
| frameshift | 1 | 12 | 1 | 14 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 1 | 471 | 246 | 4 | 723 |
Highest pathogenic variant AF is 0.0000018587452
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000386.1 | 13 | MANE Select | |
| Ensembl | ENSP00000384053.3 | 13 | MANE Select | |
| RefSeq | NP_001397756.1 | 13 | Standard | |
| Ensembl | ENSP00000385271.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Apoptosis - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- IL-5 Signaling Pathway
Biological Process
- MAPK cascade
- signal transduction
- respiratory gaseous exchange
- peptidyl-tyrosine phosphorylation
- cytokine-mediated signaling pathway
Molecular Function
- protein tyrosine kinase activity
- interleukin-3 receptor activity
- interleukin-5 receptor activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- granulocyte macrophage colony-stimulating factor receptor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000403662
- Coding exons
- 13
- Length
- 26822
- Individuals with no LoFs
- 125268
- Homozygous LoFs
- 2
- Heterozygous LoFs
- 478
- Defined
- 125748
- p
- 0.00191
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.129 | 518 | 526 | 0.984 | 0.0000325 | 5759 |
| Missense (PolyPhen) | 77 | 96.251 | 0.79999 | 1260 | ||
| Synonymous | -1.81 | 258 | 224 | 1.15 | 0.0000148 | 1901 |
| Loss of Function | 4.00 | 8 | 32.7 | 0.245 | 0.00000161 | 342 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00078 | 0.00078 | rare |
| Ashkenazi Jewish | 0.025 | 0.025 | notable |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.0011 | 0.0011 | notable |
| European (Non-Finnish) | 0.0014 | 0.0014 | notable |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.0023 | 0.0023 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: High affinity receptor for interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor.;
- Disease
- DISEASE: Pulmonary surfactant metabolism dysfunction 5 (SMDP5) [MIM:614370]: A rare lung disorder due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid- Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress. {ECO:0000269|PubMed:21075760}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.249
Intolerance Scores
- LoFtool
- 0.0832
- RVIS EVS
- -1.08
- RVIS percentile EVS
- 7.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.698
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |