CUL4B

cullin 4B, the group of Cullins

Basic information

Region (hg38): X:120505919-120604074

Links

ENSG00000158290 ∙ NCBI:8450 ∙ OMIM:300304 ∙ HGNC:2555 ∙ Uniprot:Q13620 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked intellectual disability, Cabezas type (Definitive), mode of inheritance: XLR
• X-linked intellectual disability, Cabezas type (Strong), mode of inheritance: XL
• X-linked intellectual disability, Cabezas type (Supportive), mode of inheritance: XL
• X-linked intellectual disability, Cabezas type (Definitive), mode of inheritance: XL
• X-linked intellectual disability, Cabezas type (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked, syndromic 15 (Cabezas type)	XL	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Endocrine; Musculoskeletal; Neurologic	8135271; 10978355; 11562927; 17236139; 17273978; 19377476; 20002452; 20014135; 24898194

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CUL4B gene.

• X-linked intellectual disability Cabezas type (127 variants)
• not provided (105 variants)
• Inborn genetic diseases (30 variants)
• not specified (29 variants)
• CUL4B-related condition (4 variants)
• Intellectual disability (2 variants)
• Intellectual disability;Global developmental delay;Abnormal facial shape;Seizure;Short stature (1 variants)
• CUL4B-related X-linked intellectual disability (1 variants)
• CUL4B-Related Disorder (1 variants)
• Pettigrew syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CUL4B 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			1	25	5	31
missense	1	4	78	5	2	90
nonsense	7	3				10
start loss						0
frameshift	10	4	1			15
inframe indel			6	2		8
splice donor/acceptor (+/-2bp)		3				3
splice region			7	6	1	14
non coding	2	3	5	35	24	69
Total	20	17	91	67	31

Highest pathogenic variant AF is 0.00000899

Variants in CUL4B

This is a list of pathogenic ClinVar variants found in the CUL4B region.

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

Position	Type	Phenotype	Significance	ClinVar
X-120526754-C-T		not specified	Conflicting classifications of pathogenicity (Sep 14, 2023)
X-120526771-T-TA		X-linked intellectual disability Cabezas type	Uncertain significance (May 18, 2021)
X-120526772-A-T			Uncertain significance (Dec 07, 2022)
X-120526781-G-A			Likely pathogenic (Jun 28, 2018)
X-120526797-A-C		X-linked intellectual disability Cabezas type	Uncertain significance (Feb 03, 2021)
X-120526797-A-G		Inborn genetic diseases • CUL4B-related disorder	Likely benign (Feb 17, 2022)
X-120526799-C-T		X-linked intellectual disability Cabezas type	Uncertain significance (Jan 11, 2022)
X-120526810-TAG-T			Likely pathogenic (Dec 05, 2016)
X-120526815-C-T		not specified • X-linked intellectual disability Cabezas type • Inborn genetic diseases	Benign (Jan 15, 2024)
X-120526816-C-T		Pettigrew syndrome	Likely pathogenic (Mar 16, 2016)
X-120526842-C-G			Uncertain significance (Sep 28, 2023)
X-120526874-T-G		X-linked intellectual disability Cabezas type	Likely benign (May 26, 2021)
X-120526946-C-T			Benign (Apr 10, 2019)
X-120527062-C-CT			Likely benign (Sep 02, 2019)
X-120529942-G-GT			Benign (Aug 18, 2019)
X-120530099-T-A		X-linked intellectual disability Cabezas type	Uncertain significance (Sep 09, 2023)
X-120530105-TACTGGAAATTTCA-T		X-linked intellectual disability Cabezas type	Likely pathogenic (Oct 20, 2022)
X-120530154-CTAAG-C		CUL4B-related disorder	Pathogenic (Aug 03, 2023)
X-120530171-C-G		X-linked intellectual disability Cabezas type	Uncertain significance (Sep 14, 2017)
X-120530188-T-C		X-linked intellectual disability Cabezas type	Uncertain significance (Oct 17, 2022)
X-120530212-T-C		not specified	Uncertain significance (May 04, 2022)
X-120532411-G-T		X-linked intellectual disability Cabezas type	Likely benign (Aug 22, 2022)
X-120532420-A-G			Pathogenic (Feb 14, 2022)
X-120532423-G-A			Uncertain significance (Jun 24, 2022)
X-120532453-A-C			Uncertain significance (Apr 04, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CUL4B	protein_coding	protein_coding	ENST00000404115	21	51186

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000367	125727	0	3	125730	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.77	126	314	0.401	0.0000218	6077
Missense in Polyphen		10	77.472	0.12908		1547
Synonymous	-0.522	119	112	1.06	0.00000790	1628
Loss of Function	5.48	0	35.0	0.00	0.00000254	642

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000380	0.000185
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition subunit. CUL4B may act within the complex as a scaffold protein, contributing to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. Plays a role as part of the E3 ubiquitin-protein ligase complex in polyubiquitination of CDT1, histone H2A, histone H3 and histone H4 in response to radiation- induced DNA damage. Targeted to UV damaged chromatin by DDB2 and may be important for DNA repair and DNA replication. Required for ubiquitination of cyclin E, and consequently, normal G1 cell cycle progression. Regulates the mammalian target-of-rapamycin (mTOR) pathway involved in control of cell growth, size and metabolism. Specific CUL4B regulation of the mTORC1-mediated pathway is dependent upon 26S proteasome function and requires interaction between CUL4B and MLST8. {ECO:0000269|PubMed:14578910, ECO:0000269|PubMed:16322693, ECO:0000269|PubMed:16678110, ECO:0000269|PubMed:18235224, ECO:0000269|PubMed:18593899, ECO:0000269|PubMed:19801544, ECO:0000269|PubMed:22118460}.
• Disease: DISEASE: Mental retardation, X-linked, syndromic, 15 (MRXS15) [MIM:300354]: A syndromic form of X-linked mental retardation characterized by severe intellectual deficit associated with short stature, craniofacial dysmorphism, small testes, muscle wasting in lower legs, kyphosis, joint hyperextensibility, pes cavus, small feet, and abnormalities of the toes. Additional neurologic manifestations include speech delay and impairment, tremor, seizures, gait ataxia, hyperactivity and decreased attention span. {ECO:0000269|PubMed:17236139, ECO:0000269|PubMed:17273978, ECO:0000269|PubMed:19377476, ECO:0000269|PubMed:20002452}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Nucleotide excision repair - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;miR-targeted genes in squamous cell - TarBase;Mesodermal Commitment Pathway;DNA Repair;Post-translational protein modification;Metabolism of proteins;Neddylation;Recognition of DNA damage by PCNA-containing replication complex;DNA Damage Bypass;DNA Damage Recognition in GG-NER;Formation of Incision Complex in GG-NER;Dual Incision in GG-NER;Global Genome Nucleotide Excision Repair (GG-NER);Formation of TC-NER Pre-Incision Complex;Dual incision in TC-NER;Gap-filling DNA repair synthesis and ligation in TC-NER;Transcription-Coupled Nucleotide Excision Repair (TC-NER);Nucleotide Excision Repair (Consensus)

Recessive Scores

• pRec: 0.121

Intolerance Scores

• rvis_EVS: -0.36
• rvis_percentile_EVS: 28.63

Haploinsufficiency Scores

• pHI: 0.874
• hipred: Y
• hipred_score: 0.831
• ghis: 0.652

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.559

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cul4b
• Phenotype: growth/size/body region 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); cellular phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); 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); normal 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); embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;nucleotide-excision repair, DNA damage recognition;transcription-coupled nucleotide-excision repair;nucleotide-excision repair, preincision complex stabilization;nucleotide-excision repair, preincision complex assembly;nucleotide-excision repair, DNA incision, 5'-to lesion;ubiquitin-dependent protein catabolic process;cellular response to DNA damage stimulus;proteasomal protein catabolic process;protein ubiquitination;SCF-dependent proteasomal ubiquitin-dependent protein catabolic process;neuron projection development;nucleotide-excision repair, DNA incision;histone H2A monoubiquitination;DNA damage response, detection of DNA damage;proteasome-mediated ubiquitin-dependent protein catabolic process;post-translational protein modification;positive regulation of protein catabolic process;global genome nucleotide-excision repair;UV-damage excision repair;positive regulation of G1/S transition of mitotic cell cycle
• Cellular component: nucleoplasm;cytosol;SCF ubiquitin ligase complex;cullin-RING ubiquitin ligase complex;Cul4B-RING E3 ubiquitin ligase complex;extracellular exosome;Cul4-RING E3 ubiquitin ligase complex
• Molecular function: damaged DNA binding;protein binding;ubiquitin protein ligase binding;ubiquitin protein ligase activity