CYLD

Chr 16AD

CYLD lysine 63 deubiquitinase

Also known as: BRSS, CDMT, CYLD1, CYLDI, EAC, FTDALS8, MFT, MFT1

NCBI Gene: 1540 ENSG00000083799 UniProt: Q9NQC7 OMIM: 605018

The CYLD protein functions as a deubiquitinating enzyme that cleaves specific polyubiquitin chains and negatively regulates NF-kappa-B signaling, playing critical roles in cell survival, proliferation, and immune responses. Mutations cause autosomal dominant conditions including Brooke-Spiegler syndrome, familial cylindromatosis, multiple familial trichoepithelioma, and frontotemporal dementia with or without amyotrophic lateral sclerosis. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is encodes a cytoplasmic protein with three cytoskeletal-associated protein-glycine-conserved (CAP-GLY) domains that functions as a deubiquitinating enzyme. Mutations in this gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Frontotemporal dementia and/or amyotrophic lateral sclerosis 8MIM #619132

Brooke-Spiegler syndromeMIM #605041

Cylindromatosis, familialMIM #132700

Trichoepithelioma, multiple familial, 1MIM #601606

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

125

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — CYLD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 5.65

OE 0.09 (0.04–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.55Z-score

OE missense 0.55 (0.50–0.61)

277 obs / 500.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.20)

0≤0.351.4

Missense OE?0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 44.8Missense obs/exp: 277 / 500.1Syn Z: 0.32

Background carrier burden — how many people carry a rare variant somewhere in CYLD?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

798 rare PASS variants

Rare truncating (LoF)

1 in 5,200

56 rare PASS variants

Rare synonymous (reference)

1 in 140

421 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CYLD. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 200	1 in 5,300
South Asian	~43k	1 in 120	1 in 7,200
Remaining (unassigned)	~30k	1 in 150	≈ 1 in 30,000
European (Finnish)	~27k	1 in 290	none seen
Admixed American	~22k	1 in 100	≈ 1 in 17,000
African / African American	~21k	1 in 130	1 in 3,100
East Asian	~20k	1 in 93	1 in 1,400
Ashkenazi Jewish	~13k	1 in 960	none seen
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 17 coding exons well covered in gnomAD exomes; exons 5, 6, 8, 14, 16 marginal. Genomes: all 17.? see exons ↓