16-50749874-G-A

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

1
6
12

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]

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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
CYLDNM_001378743.1 linkuse as main transcriptc.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
CYLDENST00000427738.8 linkuse as main transcriptc.176G>A p.Arg59Lys missense_variant 3/195 NM_001378743.1 ENSP00000392025 A1Q9NQC7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

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 submitterclinical testingGeneDxJul 27, 2022Not 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
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
24
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
D
LIST_S2
Uncertain
0.88
D;D;.;.;D;D;.;D;D
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.30
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.17
D
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
T
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
D
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.

Other links and lift over

hg19: chr16-50783785; API