rs587778224

Positions:

• chr16-50750042-A-G
• chr16-50750042-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378743.1(CYLD):​c.344A>G​(p.Asn115Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.80

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]

CYLD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19310841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.344A>G	p.Asn115Ser	missense_variant	3/19	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.344A>G	p.Asn115Ser	missense_variant	3/19	5	NM_001378743.1	ENSP00000392025.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T;.;T;.;T;.;.;T;.
Eigen	Benign	-0.056
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;.;.;D;D;.;D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.55	.;N;N;N;.;.;N;N;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N;N;N;N;.;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.14	T;T;T;T;.;T;T;T;D
Sift4G	Benign	0.16	T;T;T;T;T;T;T;T;T
Polyphen		0.011, 0.0070	.;B;B;B;.;.;B;B;.
Vest4		0.11, 0.10, 0.13, 0.13, 0.12, 0.10
MutPred		0.25		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.71
MPC		0.32
ClinPred		0.65	D
GERP RS		6.2
Varity_R		0.050
gMVP		0.25

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

Other links and lift over

dbSNP: rs587778224; hg19: chr16-50783953;