CBLB

Cbl proto-oncogene B, the group of Ring finger proteins

Basic information

Region (hg38): 3:105655460-105869552

Links

ENSG00000114423 ∙ NCBI:868 ∙ OMIM:604491 ∙ HGNC:1542 ∙ Uniprot:Q13191 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoimmune disease, multisystem, infantile-onset, 3 (Strong), mode of inheritance: AR
• autoimmune disease, multisystem, infantile-onset, 3 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoimmune disease, multisystem, infantile-onset, 3	AR	Allergy/Immunology/Infectious	The condition may manifest with a variety of autoimmune manifestations, and medical management (eg, with IVIG or corticosteroids) has been described in some individuals	Allergy/Immunology/Infectious	36006710

ClinVar

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

• Inborn genetic diseases (27 variants)
• not specified (15 variants)
• not provided (6 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CBLB 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				2	1	3
missense			28	1	1	30
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	28	3	2

Variants in CBLB

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

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

Position	Type	Phenotype	Significance	ClinVar
3-105659038-C-T		not specified	not provided (Sep 19, 2013)
3-105659118-G-C		not specified	Uncertain significance (Jan 17, 2023)
3-105659193-C-T		not specified	Uncertain significance (Aug 08, 2022)
3-105659203-G-C		not specified	Uncertain significance (Jan 05, 2022)
3-105659217-G-C		not specified	not provided (Sep 19, 2013)
3-105670240-T-C		CBLB-related disorder	Benign (Oct 28, 2019)
3-105670257-A-G		not specified	Uncertain significance (Dec 05, 2022)
3-105670257-A-T		not specified	Uncertain significance (May 23, 2023)
3-105670275-T-C		not specified • CBLB-related disorder	Benign (Jan 28, 2020)
3-105670302-T-C		not specified	Uncertain significance (Jan 19, 2024)
3-105670309-A-G		CBLB-related disorder	Benign (Nov 06, 2019)
3-105670346-A-G		not specified	Uncertain significance (Dec 11, 2023)
3-105678460-G-A		not specified	Uncertain significance (Dec 27, 2023)
3-105678469-C-T		not specified	Uncertain significance (Mar 06, 2023)
3-105681576-T-C		CBLB-related disorder	Benign (Oct 28, 2019)
3-105681597-A-C		not specified	Uncertain significance (Jul 19, 2022)
3-105685324-C-G		not specified	Uncertain significance (Oct 03, 2022)
3-105685345-A-G		not specified	Uncertain significance (Oct 04, 2022)
3-105685347-T-C		not specified	Uncertain significance (Jul 05, 2023)
3-105685406-A-T		not specified	Uncertain significance (Mar 04, 2024)
3-105685411-C-T		not specified	Uncertain significance (Dec 27, 2023)
3-105685414-C-G		not specified	Uncertain significance (May 08, 2023)
3-105685454-C-T		CBLB-related disorder	Benign/Likely benign (Mar 01, 2023)
3-105693522-G-C		not specified	Uncertain significance (Jan 31, 2024)
3-105693531-G-A		not specified	Uncertain significance (Apr 07, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CBLB	protein_coding	protein_coding	ENST00000264122	18	214092

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.998	0.00175	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.29	460	545	0.844	0.0000298	6406
Missense in Polyphen		151	222.53	0.67856		2608
Synonymous	-0.525	199	190	1.05	0.0000100	1942
Loss of Function	5.59	7	49.4	0.142	0.00000287	580

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000119	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000797	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000166	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B- cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T- cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. {ECO:0000269|PubMed:10022120, ECO:0000269|PubMed:10086340, ECO:0000269|PubMed:11087752, ECO:0000269|PubMed:11526404, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:20525694}.
• Pathway: T cell receptor signaling pathway - Homo sapiens (human);Endocytosis - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Measles - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Angiopoietin Like Protein 8 Regulatory Pathway;EGF-EGFR Signaling Pathway;Insulin Signaling;T-Cell antigen Receptor (TCR) Signaling Pathway;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;GPCR Adenosine A2A receptor;Signaling by the B Cell Receptor (BCR);TCR;Immune System;Adaptive Immune System;KitReceptor;Antigen processing: Ubiquitination & Proteasome degradation;BCR;Class I MHC mediated antigen processing & presentation;GPCR signaling-G alpha s PKA and ERK;EGFR1;IL-7;CD40/CD40L signaling;Fc-epsilon receptor I signaling in mast cells;Internalization of ErbB1;Calcineurin-regulated NFAT-dependent transcription in lymphocytes (Consensus)

Recessive Scores

• pRec: 0.382

Intolerance Scores

• loftool: 0.104
• rvis_EVS: -0.84
• rvis_percentile_EVS: 11.4

Haploinsufficiency Scores

• pHI: 0.485
• hipred: Y
• hipred_score: 0.756
• ghis: 0.534

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.859

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cblb
• Phenotype: immune system phenotype; liver/biliary system 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); 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); 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); growth/size/body region phenotype

Gene ontology

• Biological process: NLS-bearing protein import into nucleus;signal transduction;cell surface receptor signaling pathway;negative regulation of epidermal growth factor-activated receptor activity;protein ubiquitination;regulation of platelet-derived growth factor receptor-alpha signaling pathway
• Cellular component: nucleoplasm;cytosol;plasma membrane;membrane raft
• Molecular function: phosphotyrosine residue binding;calcium ion binding;protein binding;zinc ion binding;SH3 domain binding;receptor tyrosine kinase binding;ubiquitin protein ligase activity