16-50784421-T-C

Variant names:

• chr16-50784421-T-C
• NM_001378743.1:c.1919T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378743.1(CYLD):​c.1919T>C​(p.Leu640Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L640L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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]

ENSG00000260616 (HGNC:56848): (CYLD antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.1919T>C	p.Leu640Pro	missense_variant	Exon 12 of 19	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.1919T>C	p.Leu640Pro	missense_variant	Exon 12 of 19	5	NM_001378743.1	ENSP00000392025.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 640 of the CYLD protein (p.Leu640Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CYLD-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYLD protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	.;T;.;T;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;.;D;.;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.5	.;M;.;.;.;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.5	D;D;D;.;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;.
Vest4		0.99
MutPred		0.65		.;Loss of stability (P = 0.0063);.;.;.;Loss of stability (P = 0.0063);.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.99

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: chr16-50818332;