16-50749757-T-G
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_001378743.1(CYLD):āc.59T>Gā(p.Ile20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 32)
Exomes š: 0.000027 ( 0 hom. )
Consequence
CYLD
NM_001378743.1 missense
NM_001378743.1 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 1.80
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
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=0.2541011).
BP6
Variant 16-50749757-T-G is Benign according to our data. Variant chr16-50749757-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319497.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CYLD | NM_001378743.1 | c.59T>G | p.Ile20Ser | 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.59T>G | p.Ile20Ser | missense_variant | 3/19 | 5 | NM_001378743.1 | ENSP00000392025 | A1 |
Frequencies
GnomAD3 genomes 0.0000526 AC: 8AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000402 AC: 10AN: 249042Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135150
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461538Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727078
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GnomAD4 genome 0.0000526 AC: 8AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 02, 2023 | - - |
Familial cylindromatosis Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Familial multiple trichoepitheliomata Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Brooke-Spiegler syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;.;T;.;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;.;.;T;T;T;.;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;L;L;.;.;.;L;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;.;N;D;N;N;N
REVEL
Uncertain
Sift
Benign
T;D;D;D;.;T;T;D;D;D
Sift4G
Uncertain
T;D;D;D;D;T;D;D;D;T
Polyphen
0.14, 0.026
.;B;B;B;.;.;.;B;B;.
Vest4
0.25, 0.26, 0.48, 0.25, 0.25, 0.26, 0.24
MutPred
Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);Gain of disorder (P = 0.016);
MVP
MPC
0.60
ClinPred
T
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at