CYLD

CYLD lysine 63 deubiquitinase, the group of Ubiquitin specific peptidases|MicroRNA protein coding host genes

Basic information

Region (hg38): 16:50742049-50801935

Previous symbols: [ "CYLD1" ]

Links

ENSG00000083799 ∙ NCBI:1540 ∙ OMIM:605018 ∙ HGNC:2584 ∙ Uniprot:Q9NQC7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial cylindromatosis (Strong), mode of inheritance: AD
• trichoepithelioma, multiple familial, 1 (Strong), mode of inheritance: AD
• Brooke-Spiegler syndrome (Definitive), mode of inheritance: AD
• familial cylindromatosis (Supportive), mode of inheritance: AD
• familial multiple trichoepithelioma (Supportive), mode of inheritance: AD
• amyotrophic lateral sclerosis (Limited), mode of inheritance: AD
• familial cylindromatosis (Definitive), mode of inheritance: AD
• Brooke-Spiegler syndrome (Strong), mode of inheritance: AD
• frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (Strong), mode of inheritance: AD
• Brooke-Spiegler syndrome (Definitive), mode of inheritance: AD
• frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brooke-Spiegler syndrome; Cylindromatosis, familial; Trichoepithelioma, multiple familial, 1	AD	Dermatologic; Oncologic	The conditions can include a number of types of cancerous lesions for which surveillance/treatment (including surgical management) may be beneficial; In familial trichoepithelioma, skin lesions can degenerate into basal cell carcinoma; In Cylindromatosis, familial, childhood tumors have been reported, and neoplasms may undergo malignant transformation; Individuals are at risk of salivary/parotid adenocarcinoma	Dermatologic; Neurologic; Oncologic	8436650; 7684205; 10835629; 11703297; 12190880; 14632188; 12950348; 15854031; 16307661; 16922728; 18234730; 19076795; 19807742; 19917957; 20151946; 20972631; 21712687; 22049921; 22588548; 22689134; 22296260; 22882113; 23249834; 23260808; 23567228; 23694822; 32185393; 32666117

ClinVar

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

• Familial cylindromatosis (140 variants)
• Brooke-Spiegler syndrome (127 variants)
• Familial multiple trichoepitheliomata (111 variants)
• not provided (87 variants)
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (50 variants)
• not specified (9 variants)
• Inborn genetic diseases (7 variants)
• Trichoepithelioma, multiple familial, 2 (6 variants)
• Trichoepithelioma, multiple familial, 1 (5 variants)
• CYLD-related condition (3 variants)
• Ovarian cancer (2 variants)
• Familial cylindromatosis;Trichoepithelioma, multiple familial, 1;Brooke-Spiegler syndrome (1 variants)
• Trichoepithelioma, multiple familial, 1;Frontotemporal dementia and/or amyotrophic lateral sclerosis 8;Familial cylindromatosis;Brooke-Spiegler syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CYLD 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			4	19	4	27
missense	2		68	2	4	76
nonsense	9					9
start loss						0
frameshift	13	4				17
inframe indel						0
splice donor/acceptor (+/-2bp)	3	1	1			5
splice region	1		2	1	1	5
non coding			62	14	56	132
Total	27	5	135	35	64

Highest pathogenic variant AF is 0.00000657

Variants in CYLD

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

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

Position	Type	Phenotype	Significance	ClinVar
16-50742051-T-C		Brooke-Spiegler syndrome • Familial cylindromatosis • Familial multiple trichoepitheliomata	Uncertain significance (Jan 12, 2018)
16-50742099-G-C		Brooke-Spiegler syndrome • Familial multiple trichoepitheliomata • Familial cylindromatosis	Uncertain significance (Jan 13, 2018)
16-50742113-C-G		Familial multiple trichoepitheliomata • Brooke-Spiegler syndrome • Familial cylindromatosis	Uncertain significance (Jan 12, 2018)
16-50742256-C-T			Benign (Jul 20, 2018)
16-50744829-A-G		Brooke-Spiegler syndrome • Familial multiple trichoepitheliomata • Familial cylindromatosis	Uncertain significance (Jan 13, 2018)
16-50749517-A-G			Benign (Jun 23, 2018)
16-50749676-A-C		Familial multiple trichoepitheliomata • Brooke-Spiegler syndrome • Familial cylindromatosis	Uncertain significance (Jan 13, 2018)
16-50749722-A-C			Uncertain significance (Dec 20, 2023)
16-50749738-C-T		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
16-50749753-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (Oct 31, 2023)
16-50749757-T-G		Brooke-Spiegler syndrome • Familial multiple trichoepitheliomata • Familial cylindromatosis • Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Conflicting classifications of pathogenicity (Jun 28, 2023)
16-50749764-C-T			Likely benign (Mar 29, 2018)
16-50749768-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (May 26, 2023)
16-50749785-C-T			Benign/Likely benign (Dec 24, 2023)
16-50749823-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (Oct 19, 2023)
16-50749824-G-A		Familial cylindromatosis • Familial multiple trichoepitheliomata • Brooke-Spiegler syndrome	Benign (Jan 13, 2018)
16-50749855-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (Oct 20, 2023)
16-50749856-G-A			Uncertain significance (Dec 05, 2023)
16-50749868-A-G		Brooke-Spiegler syndrome	Uncertain significance (Jan 26, 2021)
16-50749874-G-A			Uncertain significance (Jul 27, 2022)
16-50749902-T-G		Inborn genetic diseases	Uncertain significance (Dec 07, 2023)
16-50749906-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (Dec 17, 2023)
16-50749939-G-A		Inborn genetic diseases	Uncertain significance (Nov 27, 2023)
16-50749939-G-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (Aug 30, 2023)
16-50749972-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Uncertain significance (Jul 07, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CYLD	protein_coding	protein_coding	ENST00000427738	17	59886

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000692	124788	0	7	124795	0.0000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.55	277	500	0.554	0.0000255	6275
Missense in Polyphen		79	180.53	0.43761		2315
Synonymous	0.323	178	184	0.970	0.0000102	1795
Loss of Function	5.65	4	44.8	0.0893	0.00000207	616

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000531	0.0000530
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF- kappa-B activation and TNF-alpha-induced necroptosis (PubMed:18636086, PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049, PubMed:29291351, PubMed:18313383). Plays an important role in the regulation of pathways leading to NF-kappa-B activation (PubMed:12917689, PubMed:12917691). Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation (PubMed:12917690). Negative regulator of Wnt signaling (PubMed:20227366). Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules (PubMed:19893491). Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis (PubMed:18222923, PubMed:20194890). Required for normal cell cycle progress and normal cytokinesis (PubMed:17495026, PubMed:19893491). Inhibits nuclear translocation of NF-kappa-B (PubMed:18636086). Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation (PubMed:18636086). Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells (By similarity). Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity). Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation (By similarity). Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha- induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins (PubMed:26997266, PubMed:26670046, PubMed:27458237, PubMed:27591049). Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (PubMed:26997266). Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (PubMed:29291351). {ECO:0000250|UniProtKB:Q80TQ2, ECO:0000269|PubMed:12917689, ECO:0000269|PubMed:12917690, ECO:0000269|PubMed:12917691, ECO:0000269|PubMed:17495026, ECO:0000269|PubMed:18222923, ECO:0000269|PubMed:18313383, ECO:0000269|PubMed:18636086, ECO:0000269|PubMed:19893491, ECO:0000269|PubMed:20194890, ECO:0000269|PubMed:20227366, ECO:0000269|PubMed:26670046, ECO:0000269|PubMed:26997266, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27591049, ECO:0000269|PubMed:29291351}.
• Disease: DISEASE: Cylindromatosis, familial (FCYL) [MIM:132700]: A disorder characterized by multiple skin tumors that develop from skin appendages, such as hair follicles and sweat glands. Affected individuals typically develop large numbers of tumors called cylindromas that arise predominantly in hairy parts of the body with approximately 90% on the head and neck. In severely affected individuals, cylindromas may combine into a confluent mass which may ulcerate or become infected (turban tumor syndrome). Individuals with familial cylindromatosis occasionally develop other types of tumors including spiradenomas that begin in sweat glands, and trichoepitheliomas arising from hair follicles. {ECO:0000269|PubMed:12190880, ECO:0000269|PubMed:16922728}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple familial trichoepithelioma 1 (MFT1) [MIM:601606]: Autosomal dominant dermatosis characterized by the presence of many skin tumors predominantly on the face. Since histologic examination shows dermal aggregates of basaloid cells with connection to or differentiation toward hair follicles, this disorder has been thought to represent a benign hamartoma of the pilosebaceous apparatus. Trichoepitheliomas can degenerate into basal cell carcinoma. {ECO:0000269|PubMed:14632188, ECO:0000269|PubMed:16307661, ECO:0000269|PubMed:16922728}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brooke-Spiegler syndrome (BRSS) [MIM:605041]: An autosomal dominant disorder characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life. {ECO:0000269|PubMed:12190880, ECO:0000269|PubMed:12950348, ECO:0000269|PubMed:14632188, ECO:0000269|PubMed:15854031}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Necroptosis - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;RIG-I-like Receptor Signaling;Signal Transduction;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;TNFR1-induced NFkappaB signaling pathway;TNFR1-induced proapoptotic signaling;EGFR1;TNF signaling;Ub-specific processing proteases;Deubiquitination;Death Receptor Signalling;Regulation of TNFR1 signaling;Canonical NF-kappaB pathway;RANKL;TNF receptor signaling pathway (Consensus)

Recessive Scores

• pRec: 0.309

Intolerance Scores

• loftool: 0.0672
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.47

Haploinsufficiency Scores

• pHI: 0.700
• hipred: Y
• hipred_score: 0.816
• ghis: 0.618

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.916

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cyld
• Phenotype: cellular phenotype; homeostasis/metabolism 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; endocrine/exocrine gland phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; limbs/digits/tail phenotype; digestive/alimentary 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); normal phenotype; hematopoietic system phenotype; neoplasm

Zebrafish Information Network

• Gene name: cyldb
• Affected structure: pharyngeal arch cartilage
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: ubiquitin-dependent protein catabolic process;cell cycle;regulation of mitotic cell cycle;regulation of tumor necrosis factor-mediated signaling pathway;Wnt signaling pathway;protein deubiquitination;negative regulation of NF-kappaB transcription factor activity;negative regulation of type I interferon production;CD4-positive or CD8-positive, alpha-beta T cell lineage commitment;regulation of protein binding;innate immune response;regulation of B cell differentiation;positive regulation of T cell differentiation;negative regulation of JNK cascade;homeostasis of number of cells;regulation of inflammatory response;positive regulation of T cell receptor signaling pathway;regulation of necroptotic process;necroptotic process;nucleotide-binding oligomerization domain containing signaling pathway;regulation of microtubule cytoskeleton organization;protein K63-linked deubiquitination;protein K48-linked deubiquitination;negative regulation of canonical Wnt signaling pathway;ripoptosome assembly involved in necroptotic process;negative regulation of NIK/NF-kappaB signaling;regulation of cilium assembly;negative regulation of p38MAPK cascade;positive regulation of cellular protein localization;protein linear deubiquitination;positive regulation of extrinsic apoptotic signaling pathway;regulation of intrinsic apoptotic signaling pathway
• Cellular component: centrosome;spindle;cytosol;cytoplasmic microtubule;midbody;extrinsic component of cytoplasmic side of plasma membrane;ciliary basal body;perinuclear region of cytoplasm;ciliary tip
• Molecular function: thiol-dependent ubiquitin-specific protease activity;protein binding;zinc ion binding;protein kinase binding;thiol-dependent ubiquitinyl hydrolase activity;Lys63-specific deubiquitinase activity;proline-rich region binding;Lys48-specific deubiquitinase activity