16-50776244-G-T

Position:

• chr16-50776244-G-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.988G>T​(p.Gly330Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G330R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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=0.19789237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYLD	NM_001378743.1	c.988G>T	p.Gly330Cys	missense_variant	7/19	ENST00000427738.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYLD	ENST00000427738.8	c.988G>T	p.Gly330Cys	missense_variant	7/19	5	NM_001378743.1	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.089
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;.;.;D;.;D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.89	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N;N;.;N;N;N
Sift	Uncertain	0.012	D;D;D;.;D;D;D
Sift4G	Uncertain	0.050	T;D;T;D;T;D;T
Polyphen		0.74	P;P;P;.;P;P;.
Vest4		0.38
MutPred		0.26		.;Gain of methylation at K329 (P = 0.0158);.;.;.;Gain of methylation at K329 (P = 0.0158);.;
MVP		0.46
MPC		0.70
ClinPred		0.73	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.50

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: chr16-50810155;