16-50749738-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 14/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CYLD
• BP4: Computational evidence support a benign effect (MetaRNN=0.13844883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYLD	NM_001378743.1	c.40C>T	p.Pro14Ser	missense_variant	3/19	ENST00000427738.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYLD	ENST00000427738.8	c.40C>T	p.Pro14Ser	missense_variant	3/19	5	NM_001378743.1	A1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.40C>T (p.P14S) alteration is located in exon 4 (coding exon 1) of the CYLD gene. This alteration results from a C to T substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;T;.;.;.;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T;T;.;.;T;T;T;.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.92	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.26	N;N;N;N;.;N;D;N;N;N
Sift	Benign	0.56	T;T;T;T;.;T;T;T;T;D
Sift4G	Benign	0.79	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	.;B;B;B;.;.;.;B;B;.
Vest4		0.13, 0.13, 0.12, 0.11, 0.14, 0.14
MutPred		0.26		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.76
MPC		0.40
ClinPred		0.14	T
GERP RS		3.7
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

Publications

No publications associated with this variant yet.

Other links and lift over

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