rs121908389

Positions:

• chr16-50791689-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001378743.1(CYLD):​c.2240A>G​(p.Glu747Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYLD NM_001378743.1 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.89

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CYLD. . Gene score misZ 3.5455 (greater than the threshold 3.09). Trascript score misZ 4.7021 (greater than threshold 3.09). GenCC has associacion of gene with familial multiple trichoepithelioma, familial cylindromatosis, amyotrophic lateral sclerosis, Brooke-Spiegler syndrome, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, trichoepithelioma, multiple familial, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 16-50791689-A-G is Pathogenic according to our data. Variant chr16-50791689-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5258.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.2240A>G	p.Glu747Gly	missense_variant, splice_region_variant	15/19	ENST00000427738.8	NP_001365672.1
LOC105371251	XR_933542.3	n.457-7500T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.2240A>G	p.Glu747Gly	missense_variant, splice_region_variant	15/19	5	NM_001378743.1	ENSP00000392025	A1
	ENST00000564510.1	n.457-7500T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Familial multiple trichoepitheliomata Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Brooke-Spiegler syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;T;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D;.;.;D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	.;M;.;.;.;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.3	D;D;D;.;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D;D;D;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.98	D;.;D;.;D;.;.
Vest4		0.77
MutPred		0.69		Gain of sheet (P = 0.0043);.;Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);.;.;
MVP		0.87
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908389; hg19: chr16-50825600;