chr16-50749738-C-T

Variant names:

• chr16-50749738-C-T
• rs1966467862
• NM_001378743.1:c.40C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378743.1(CYLD):​c.40C>T​(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13844883).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378743.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	NM_001378743.1	MANE Select	c.40C>T	p.Pro14Ser	missense	Exon 3 of 19	NP_001365672.1	Q9NQC7-1
	CYLD	NM_015247.3		c.40C>T	p.Pro14Ser	missense	Exon 4 of 20	NP_056062.1	Q9NQC7-1
	CYLD	NM_001042355.2		c.40C>T	p.Pro14Ser	missense	Exon 3 of 18	NP_001035814.1	Q9NQC7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	ENST00000427738.8	TSL:5 MANE Select	c.40C>T	p.Pro14Ser	missense	Exon 3 of 19	ENSP00000392025.3	Q9NQC7-1
	CYLD	ENST00000398568.6	TSL:1	c.40C>T	p.Pro14Ser	missense	Exon 3 of 18	ENSP00000381574.2	Q9NQC7-2
	CYLD	ENST00000569418.5	TSL:1	c.40C>T	p.Pro14Ser	missense	Exon 3 of 18	ENSP00000457576.1	Q9NQC7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461524 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727060

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	11
DANN	Benign	0.74
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.22
Sift	Benign	0.56	T
Sift4G	Benign	0.79	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.26		Loss of sheet (P = 0.0457)
MVP		0.76
MPC		0.40
ClinPred		0.14	T
GERP RS		3.7
PromoterAI		-0.020	Neutral
Varity_R		0.034
gMVP		0.30

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: rs1966467862; hg19: chr16-50783649; COSMIC: COSV105144909; COSMIC: COSV105144909;