16-50779818-G-A
Position:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001378743.1(CYLD):c.1292G>A(p.Gly431Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000425 in 1,613,352 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00044 ( 9 hom. )
Consequence
CYLD
NM_001378743.1 missense
NM_001378743.1 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 6.10
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 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=0.0057254434).
BP6
Variant 16-50779818-G-A is Benign according to our data. Variant chr16-50779818-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50779818-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000237 (36/151584) while in subpopulation SAS AF= 0.00749 (36/4804). AF 95% confidence interval is 0.00556. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 36 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CYLD | NM_001378743.1 | c.1292G>A | p.Gly431Glu | missense_variant | 9/19 | ENST00000427738.8 | NP_001365672.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CYLD | ENST00000427738.8 | c.1292G>A | p.Gly431Glu | missense_variant | 9/19 | 5 | NM_001378743.1 | ENSP00000392025.3 |
Frequencies
GnomAD3 genomes 0.000238 AC: 36AN: 151464Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
36
AN:
151464
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000903 AC: 225AN: 249278Hom.: 4 AF XY: 0.00133 AC XY: 180AN XY: 135244
GnomAD3 exomes
AF:
AC:
225
AN:
249278
Hom.:
AF XY:
AC XY:
180
AN XY:
135244
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000444 AC: 649AN: 1461768Hom.: 9 Cov.: 32 AF XY: 0.000668 AC XY: 486AN XY: 727206
GnomAD4 exome
AF:
AC:
649
AN:
1461768
Hom.:
Cov.:
32
AF XY:
AC XY:
486
AN XY:
727206
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000237 AC: 36AN: 151584Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 30AN XY: 74008
GnomAD4 genome
AF:
AC:
36
AN:
151584
Hom.:
Cov.:
32
AF XY:
AC XY:
30
AN XY:
74008
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
121
Asia WGS
AF:
AC:
13
AN:
3478
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial multiple trichoepitheliomata Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 cylindromatosis Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Trichoepithelioma, multiple familial, 1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Brooke-Spiegler syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;.;.;.;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.;N;N
REVEL
Uncertain
Sift
Benign
D;D;D;.;D;D
Sift4G
Benign
T;T;T;T;T;T
Polyphen
D;D;D;.;D;D
Vest4
MVP
MPC
1.1
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at