rs121908388

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001378743.1(CYLD):​c.2272C>T​(p.Arg758*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

CYLD
NM_001378743.1 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 5.82
Variant links:
Genes affected
CYLD (HGNC:2584): (CYLD lysine 63 deubiquitinase) 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]
ENSG00000260616 (HGNC:56848): (CYLD antisense RNA 2)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-50792627-C-T is Pathogenic according to our data. Variant chr16-50792627-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50792627-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYLDNM_001378743.1 linkc.2272C>T p.Arg758* stop_gained Exon 16 of 19 ENST00000427738.8 NP_001365672.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYLDENST00000427738.8 linkc.2272C>T p.Arg758* stop_gained Exon 16 of 19 5 NM_001378743.1 ENSP00000392025.3 Q9NQC7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cylindromatosis Pathogenic:1
Jun 01, 2000
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
Aug 27, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in individuals with clinical features of CYLD-related cutaneous syndrome referred for genetic testing at GeneDx and in published literature (Bignell et al., 2000); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21389835, 17083363, 24728327, 26861065, 23249834, 24628357, 34744449, 19462465, 20972631, 31093340, 23584127, 15541090, 10835629) -

Brooke-Spiegler syndrome Pathogenic:1
Jun 04, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS4, PM2, PP4 -

not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.93
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908388; hg19: chr16-50826538; COSMIC: COSV61092791; COSMIC: COSV61092791; API