CBL

Cbl proto-oncogene, the group of Ring finger proteins

Basic information

Region (hg38): 11:119206297-119313926

Previous symbols: [ "CBL2" ]

Links

ENSG00000110395 ∙ NCBI:867 ∙ OMIM:165360 ∙ HGNC:1541 ∙ Uniprot:P22681 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• CBL-related disorder (Definitive), mode of inheritance: AD
• CBL-related disorder (Definitive), mode of inheritance: AD
• CBL-related disorder (Strong), mode of inheritance: AD
• Noonan syndrome (Supportive), mode of inheritance: AD
• CBL-related disorder (Supportive), mode of inheritance: AD
• CBL-related disorder (Strong), mode of inheritance: AD
• juvenile myelomonocytic leukemia (Strong), mode of inheritance: AD
• CBL-related disorder (Strong), mode of inheritance: AD
• CBL-related disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia; Juvenile myelomonocytic leukemia, familial	AD	Cardiovascular; Oncologic	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	Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic	20694012; 20543203; 25358541; 25939664

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CBL gene.

• RASopathy (903 variants)
• CBL-related disorder (274 variants)
• not provided (251 variants)
• not specified (186 variants)
• Cardiovascular phenotype (185 variants)
• Noonan syndrome and Noonan-related syndrome (61 variants)
• Juvenile myelomonocytic leukemia;CBL-related disorder (33 variants)
• Juvenile myelomonocytic leukemia (28 variants)
• Inborn genetic diseases (27 variants)
• Noonan-like syndrome (21 variants)
• CBL-related condition (18 variants)
• CBL-related disorder;Juvenile myelomonocytic leukemia (15 variants)
• Noonan syndrome-like disorder with juvenile myelomonocytic leukemia (6 variants)
• Noonan syndrome (5 variants)
• Stroke disorder (4 variants)
• Fragile site 11b;CBL-related disorder (3 variants)
• See cases (3 variants)
• Hematologic neoplasm (2 variants)
• Global developmental delay (1 variants)
• Rhabdomyosarcoma (1 variants)
• Noonan syndrome 1 (1 variants)
• Neurodevelopmental disorder (1 variants)
• Microcephaly (1 variants)
• CBL-related disorder;Fragile site 11b (1 variants)
• Hepatosplenomegaly (1 variants)
• Myeloproliferative disorder (1 variants)
• Malignant germ cell tumor of ovary (1 variants)
• Epilepsy, early-onset (1 variants)
• Left ventricular noncompaction cardiomyopathy (1 variants)
• B lymphoblastic leukemia lymphoma with hyperdiploidy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CBL gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	228	5	242
missense	2	11	514	13	3	543
nonsense	1	1	11			13
start loss			1			1
frameshift			18			18
inframe indel	2	2	22	3		29
splice donor/acceptor (+/-2bp)	3	5	10			18
splice region			21	25	1	47
non coding			126	137	81	344
Total	8	19	711	381	89

Highest pathogenic variant AF is 0.00000658

Variants in CBL

This is a list of pathogenic ClinVar variants found in the CBL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-119206302-C-T			Likely benign (Aug 19, 2019)
11-119206305-C-T		CBL-related disorder	Uncertain significance (Jan 13, 2018)
11-119206312-G-A		CBL-related disorder	Benign (Jan 12, 2018)
11-119206322-G-A		CBL-related disorder	Benign/Likely benign (Aug 15, 2019)
11-119206322-G-GCGA		CBL-related disorder	Uncertain significance (Jan 10, 2024)
11-119206335-C-T		CBL-related disorder	Uncertain significance (Jan 13, 2018)
11-119206339-C-T		CBL-related disorder	Uncertain significance (Jan 13, 2018)
11-119206371-T-TCGAGC			Benign (Aug 01, 2017)
11-119206377-C-T		CBL-related disorder	Uncertain significance (Jan 13, 2018)
11-119206392-G-C			Benign (Mar 03, 2015)
11-119206413-A-G		not specified • CBL-related disorder	Conflicting classifications of pathogenicity (Sep 21, 2023)
11-119206418-A-G		RASopathy	Uncertain significance (Nov 01, 2022)
11-119206423-C-G		RASopathy • Noonan syndrome and Noonan-related syndrome • Juvenile myelomonocytic leukemia • Cardiovascular phenotype	Likely benign (Dec 31, 2023)
11-119206423-C-T		Cardiovascular phenotype • RASopathy	Likely benign (Sep 03, 2022)
11-119206425-G-T		RASopathy	Uncertain significance (Dec 20, 2022)
11-119206429-C-T		not specified • RASopathy • Cardiovascular phenotype • Juvenile myelomonocytic leukemia	Benign/Likely benign (Jan 28, 2024)
11-119206433-A-C		Noonan syndrome and Noonan-related syndrome • RASopathy • Cardiovascular phenotype	Uncertain significance (Aug 10, 2023)
11-119206435-G-T		Cardiovascular phenotype • not specified	Uncertain significance (Apr 10, 2023)
11-119206440-G-A		RASopathy • Cardiovascular phenotype	Uncertain significance (Jun 06, 2023)
11-119206442-T-C		RASopathy	Uncertain significance (Aug 30, 2021)
11-119206443-C-T		RASopathy	Uncertain significance (Jun 14, 2023)
11-119206447-G-A		RASopathy	Likely benign (Nov 22, 2021)
11-119206448-G-T		Cardiovascular phenotype	Uncertain significance (Nov 02, 2022)
11-119206449-C-A		RASopathy	Uncertain significance (Oct 31, 2022)
11-119206449-C-G		Cardiovascular phenotype	Uncertain significance (Mar 03, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CBL	protein_coding	protein_coding	ENST00000264033	16	102108

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000609	0.999	125709	0	39	125748	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.03	432	497	0.870	0.0000283	5901
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000383	0.000383
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000163	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000220	0.000141
Middle Eastern	0.000163	0.000163
South Asian	0.000229	0.000229
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);EGF-Ncore;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Prolactin Signaling Pathway;Signaling Pathways in Glioblastoma;B Cell Receptor Signaling Pathway;Integrated Lung Cancer Pathway;JAK-STAT;IL-3 Signaling Pathway;Kit receptor signaling pathway;Association Between Physico-Chemical Features and Toxicity Associated Pathways;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;IL-4 Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;MET in type 1 papillary renal cell carcinoma;EGF-EGFR Signaling Pathway;Insulin Signaling;IL-2 Signaling Pathway;Interferon type I signaling pathways;T-Cell antigen Receptor (TCR) Signaling Pathway;Signaling by PTK6;Negative regulation of FGFR2 signaling;Signaling by FGFR2;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;Disease;Negative regulation of FGFR3 signaling;Signaling by FGFR3;Signal Transduction;Signaling by Interleukins;Negative regulation of FGFR4 signaling;Signaling by FGFR4;Signaling by FGFR;Spry regulation of FGF signaling;Vesicle-mediated transport;il-2 receptor beta chain in t cell activation;sprouty regulation of tyrosine kinase signals;cbl mediated ligand-induced downregulation of egf receptors pathway;Membrane Trafficking;Cytokine Signaling in Immune system;GPCR Adenosine A2A receptor;Signaling by the B Cell Receptor (BCR);TCR;Infectious disease;Immune System;Adaptive Immune System;KitReceptor;PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1;BCR;EGFR downregulation;Signaling by EGFR;GPCR signaling-G alpha s PKA and ERK;Regulation of KIT signaling;Clathrin-mediated endocytosis;EGFR1;IL2;Signaling by Non-Receptor Tyrosine Kinases;IL3;Cargo recognition for clathrin-mediated endocytosis;Signaling by EGFR in Cancer;IFN-gamma pathway;IL4;EPO signaling pathway;Signaling by SCF-KIT;IL5;IL6;Negative regulation of MET activity;Signaling by MET;Signaling by Receptor Tyrosine Kinases;Signaling by TGF-beta Receptor Complex;Signaling by TGF-beta family members;Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants;Signaling by Ligand-Responsive EGFR Variants in Cancer;TGF-beta receptor signaling activates SMADs;Insulin Pathway;Diseases of signal transduction;CDC42 signaling events;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Fc-epsilon receptor I signaling in mast cells;IL8- and CXCR1-mediated signaling events;Internalization of ErbB1;TCR signaling in naïve CD8+ T cells;Signaling events mediated by Stem cell factor receptor (c-Kit);PDGFR-beta signaling pathway;IL4-mediated signaling events;Interleukin-6 signaling;Interleukin-6 family signaling;IL8- and CXCR2-mediated signaling events;FGF signaling pathway;Signaling events mediated by VEGFR1 and VEGFR2;TCR signaling in naïve CD4+ T cells;Integrins in angiogenesis;EPHA forward signaling;VEGFR1 specific signals;Negative regulation of FGFR1 signaling;Signaling by FGFR1;Regulation of signaling by CBL;Interleukin-3, 5 and GM-CSF signaling;InlB-mediated entry of Listeria monocytogenes into host cell;Listeria monocytogenes entry into host cells (Consensus)

Recessive Scores

• pRec: 0.478

Intolerance Scores

• loftool: 0.302
• rvis_EVS: -1.04
• rvis_percentile_EVS: 7.77

Haploinsufficiency Scores

• pHI: 0.997
• hipred: Y
• hipred_score: 0.674
• ghis: 0.613

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Cbl
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; craniofacial phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; immune system phenotype; hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); pigmentation phenotype

Zebrafish Information Network

• Gene name: cbl
• Affected structure: myeloid cell
• Phenotype tag: abnormal
• Phenotype quality: increased occurrence

Gene ontology

• Biological process: protein polyubiquitination;ubiquitin-dependent protein catabolic process;protein monoubiquitination;cellular response to DNA damage stimulus;signal transduction;cell surface receptor signaling pathway;epidermal growth factor receptor signaling pathway;negative regulation of epidermal growth factor-activated receptor activity;transforming growth factor beta receptor signaling pathway;fibroblast growth factor receptor signaling pathway;male gonad development;response to gamma radiation;positive regulation of phosphatidylinositol 3-kinase signaling;response to activity;protein ubiquitination;cytokine-mediated signaling pathway;regulation of Rap protein signal transduction;response to testosterone;entry of bacterium into host cell;cellular response to platelet-derived growth factor stimulus;negative regulation of epidermal growth factor receptor signaling pathway;response to starvation;negative regulation of apoptotic process;mast cell degranulation;response to ethanol;positive regulation of epidermal growth factor receptor signaling pathway;positive regulation of receptor-mediated endocytosis;membrane organization;interleukin-6-mediated signaling pathway;neuron death;cellular response to epidermal growth factor stimulus;cellular response to oxygen-glucose deprivation;negative regulation of neuron death;cellular response to nerve growth factor stimulus;regulation of platelet-derived growth factor receptor-alpha signaling pathway
• Cellular component: Golgi apparatus;cytosol;plasma membrane;focal adhesion;cilium;flotillin complex;growth cone;mast cell granule;membrane raft;perinuclear region of cytoplasm
• Molecular function: phosphotyrosine residue binding;ubiquitin-protein transferase activity;epidermal growth factor receptor binding;calcium ion binding;protein binding;SH3 domain binding;receptor tyrosine kinase binding;phosphatidylinositol 3-kinase regulatory subunit binding;cadherin binding;ephrin receptor binding;ubiquitin protein ligase activity