Variant chr16-50749874-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001378743.1(CYLD):c.176G>A(p.Arg59Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CYLD
NM_001378743.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.61

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]

CYLD links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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=0.29971397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYLD	NM_001378743.1 linkuse as main transcript	c.176G>A	p.Arg59Lys	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 linkuse as main transcript	c.176G>A	p.Arg59Lys	missense_variant	3/19	5	NM_001378743.1	ENSP00000392025	A1	Q9NQC7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.017

T;.;T;.;T;.;.;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.029

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

D;D;.;.;D;D;.;D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.30

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.81

.;L;L;L;.;.;L;L;.

MutationTaster

Benign

0.97

D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.33

N;N;N;N;.;N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.21

T;D;D;D;.;T;D;D;D

Sift4G

Benign

0.77

T;T;T;T;T;T;T;T;T

Polyphen

0.15, 0.025

.;B;B;B;.;.;B;B;.

Vest4

0.28, 0.27, 0.33, 0.29, 0.30, 0.29, 0.27

MutPred

0.33

Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);

MVP

0.81

MPC

0.64

ClinPred

0.86

GERP RS

5.9

Varity_R

0.27

gMVP

0.39

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over