CBL
protein-codingCbl proto-oncogene, the group of Ring finger proteins
Gene summary
This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]
- CBL2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~107.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013308
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013308
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013308
Submitter: ClinGen
CBL was first reported in relation to autosomal dominant CBL-related disorders in 2010 (Martinelli et al., PMID 20619386). At least 9 variants (e.g. missense, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case level data and experimental data including a functional alteration study expressing patient variants in heterologous cell lines and two different mouse models (PMIDs 20619386, 28082680, 28209720, 20951944). CBL-related disorder is a genetic condition caused by pathogenic variants in the Cbl ubiquitin ligase gene, (CBL; HGNC:1541). Due to the proposed mechanism indicating the CBL gene's relationship to the RAS-MAPK pathway and the phenotypic presentation similar to that of the RASopathies, CBL-related disorder should be considered a RASopathy disorder. Though there is a wide spectrum of phenotypic variability, broadly, patients with CBL-related disorder have presented with developmental delay, intellectual disability, neurodevelopmental alterations, prenatal lymphatic anomalies, cardiac malformations as well as vascular anomalies particularly affecting the brain (e.g. Moya-moya arteriopathies), craniofacial features indicative of a RASopathy, hypotonia, feeding difficulties, edema of the legs, musculoskeletal and respiratory thorax abnormalities, ectodermal features including cafe-au-lait spots, immunological and hematological disorders and susceptibility to tumors diagnosed as juvenile myelomonocytic leukemia (JMML) that is usually self-remitting. Note tumor risk beyond JMML has not yet been thoroughly assessed. Due to the clinical presentation of a broad spectrum of these and other phenotypes in patients with variants in CBL, these conditions are currently defined by experts in reference to the causal gene, CBL (PMID's: 20619386, 25283271, 25358541, 28589114, 28414188, 28343148, 24458550, 29259247, 26911351, 21901340, 25952305). The mechanism for disease is unknown. In summary, CBL is definitively associated with autosomal dominant CBL-related disorder. 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 RASopathy Gene Curation Expert Panel on 1/7/2019 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0013308
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013308
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011908
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013308
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic
Intervention: Cardiovascular; Oncologic
Rationale: For Noonan syndrome, surveillance to allow early diagnosis and treatment of malignancy may reduce morbidity; The condition may also include cardiac anomalies and dysrhythmias, and appropriate surveillance and care may be beneficial; For Juvenile myelomonocytic leukemia, awareness may allow early detection and treatment of disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CBL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005188.4. 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 | 10 | 527 | 5 | 542 | ||
| missense | 3 | 40 | 1209 | 67 | 4 | 1323 |
| nonsense | 1 | 1 | 26 | 1 | 29 | |
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | 36 | 38 | ||
| splice donor/acceptor (+/-2bp) | 4 | 7 | 22 | 33 | ||
| Total | 9 | 49 | 1304 | 595 | 9 | 1966 |
Highest pathogenic variant AF is 0.000026023272
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005179.2 | 16 | MANE Select | |
| Ensembl | ENSP00000264033.3 | 16 | MANE Select | |
| Ensembl | ENSP00000489556.1 | 3 | Standard | |
| Ensembl | ENSP00000489218.1 | 17 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cbl | Danio rerio | Structure: myeloid cell Quality: increased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chronic myeloid leukemia - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- ErbB signaling pathway - Homo sapiens (human)
- Bacterial invasion of epithelial cells - Homo sapiens (human)
Biological Process
- protein polyubiquitination
- ubiquitin-dependent protein catabolic process
- protein monoubiquitination
- cellular response to DNA damage stimulus
- signal transduction
Molecular Function
- phosphotyrosine residue binding
- ubiquitin-protein transferase activity
- epidermal growth factor receptor binding
- calcium ion binding
- protein binding
Cellular Component
- Golgi apparatus
- cytosol
- plasma membrane
- focal adhesion
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264033
- Coding exons
- 16
- Length
- 102108
- Individuals with no LoFs
- 125709
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 39
- Defined
- 125748
- p
- 0.000155
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.03 | 432 | 497 | 0.870 | 0.0000283 | 5901 |
| Missense (PolyPhen) | 116 | 169.25 | 0.68538 | 1983 | ||
| Synonymous | -0.650 | 202 | 191 | 1.06 | 0.0000110 | 1823 |
| Loss of Function | 4.14 | 14 | 43.5 | 0.322 | 0.00000268 | 487 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00022 | 0.00014 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. {ECO:0000269|PubMed:10514377, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:14739300, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19689429, ECO:0000269|PubMed:21596750}.;
- Disease
- DISEASE: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. Some have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia. {ECO:0000269|PubMed:20619386, ECO:0000269|PubMed:25178484}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.478
Intolerance Scores
- LoFtool
- 0.302
- RVIS EVS
- -1.04
- RVIS percentile EVS
- 7.77
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |