16-50749722-A-C

Position:

• chr16-50749722-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001378743.1(CYLD):​c.24A>C​(p.Gln8His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CYLD. . Gene score misZ 3.5455 (greater than the threshold 3.09). Trascript score misZ 4.7021 (greater than threshold 3.09). GenCC has associacion of gene with familial multiple trichoepithelioma, familial cylindromatosis, amyotrophic lateral sclerosis, Brooke-Spiegler syndrome, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, trichoepithelioma, multiple familial, 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.24A>C	p.Gln8His	missense_variant	3/19	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.24A>C	p.Gln8His	missense_variant	3/19	5	NM_001378743.1	ENSP00000392025	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 8 of the CYLD protein (p.Gln8His). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYLD protein function with a negative 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	Benign	0.29
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.;T;.;T;.;.;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;D;D;.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.0	.;L;L;L;.;.;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N;N;N;N;.;N;D;N;N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;.;.;D;D;.
Vest4		0.60, 0.58, 0.63, 0.61, 0.55
MutPred		0.18		Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);Gain of glycosylation at S3 (P = 0.073);
MVP		0.97
MPC		1.2
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.40
gMVP		0.66

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: chr16-50783633;