rs7342715

Variant names:

• chr16-50753572-A-G
• rs7342715
• NM_001378743.1:c.808-747A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378743.1(CYLD):​c.808-747A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 152,124 control chromosomes in the GnomAD database, including 26,817 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (26817 hom., cov: 32)
• Consequence: CYLD NM_001378743.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.149
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.808-747A>G		intron_variant	Intron 4 of 18	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.808-747A>G		intron_variant	Intron 4 of 18	5	NM_001378743.1	ENSP00000392025.3

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88143 AN: 152006 Hom.: 26760 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.544

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.580 AC: 88254 AN: 152124 Hom.: 26817 Cov.: 32 AF XY: 0.576 AC XY: 42853 AN XY: 74352

African (AFR) AF: 0.753 AC: 31276 AN: 41528

American (AMR) AF: 0.494 AC: 7550 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2316 AN: 3472

East Asian (EAS) AF: 0.230 AC: 1191 AN: 5170

South Asian (SAS) AF: 0.473 AC: 2277 AN: 4810

European-Finnish (FIN) AF: 0.540 AC: 5714 AN: 10572

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 36088 AN: 67966

Other (OTH) AF: 0.540 AC: 1140 AN: 2110

Alfa AF: 0.547 Hom.: 6488

Bravo AF: 0.580

Asia WGS AF: 0.398 AC: 1384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		0.15
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: rs7342715; hg19: chr16-50787483;