16-50781521-C-T

Variant names:

• chr16-50781521-C-T
• rs1420871
• NM_001378743.1:c.1684+110C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378743.1(CYLD):​c.1684+110C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,343,566 control chromosomes in the GnomAD database, including 6,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (490 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6049 hom.)
• Consequence: CYLD NM_001378743.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.432
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Brooke-Spiegler syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial cylindromatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
• frontotemporal dementia and/or amyotrophic lateral sclerosis 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• trichoepithelioma, multiple familial, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial multiple trichoepithelioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-50781521-C-T is Benign according to our data. Variant chr16-50781521-C-T is described in ClinVar as Benign. ClinVar VariationId is 1267104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.1684+110C>T		intron_variant	Intron 10 of 18	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.1684+110C>T		intron_variant	Intron 10 of 18	5	NM_001378743.1	ENSP00000392025.3

Frequencies

GnomAD3 genomes AF: 0.0677 AC: 10290 AN: 152106 Hom.: 491 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0833

GnomAD4 exome AF: 0.0885 AC: 105457 AN: 1191342 Hom.: 6049 AF XY: 0.0947 AC XY: 56779 AN XY: 599666

African (AFR) AF: 0.0310 AC: 859 AN: 27696

American (AMR) AF: 0.0493 AC: 1850 AN: 37498

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3252 AN: 23998

East Asian (EAS) AF: 0.0643 AC: 2337 AN: 36332

South Asian (SAS) AF: 0.233 AC: 17819 AN: 76410

European-Finnish (FIN) AF: 0.0503 AC: 2289 AN: 45468

Middle Eastern (MID) AF: 0.171 AC: 624 AN: 3644

European-Non Finnish (NFE) AF: 0.0806 AC: 71658 AN: 889032

Other (OTH) AF: 0.0930 AC: 4769 AN: 51264

GnomAD4 genome AF: 0.0676 AC: 10295 AN: 152224 Hom.: 490 Cov.: 32 AF XY: 0.0695 AC XY: 5176 AN XY: 74432

African (AFR) AF: 0.0303 AC: 1257 AN: 41534

American (AMR) AF: 0.0607 AC: 929 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3470

East Asian (EAS) AF: 0.0483 AC: 250 AN: 5172

South Asian (SAS) AF: 0.234 AC: 1126 AN: 4818

European-Finnish (FIN) AF: 0.0500 AC: 530 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0801 AC: 5450 AN: 68012

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0435 Hom.: 63

Bravo AF: 0.0630

Asia WGS AF: 0.135 AC: 470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.60
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1420871; hg19: chr16-50815432; COSMIC: COSV61097347; COSMIC: COSV61097347;