rs587778226

chr16-50776244-G-Achr16-50776244-G-Cchr16-50776244-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>A(p.Gly330Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,284 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. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• 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=0.08527139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYLD	NM_001378743.1	c.988G>A	p.Gly330Ser	missense_variant	7/19	ENST00000427738.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYLD	ENST00000427738.8	c.988G>A	p.Gly330Ser	missense_variant	7/19	5	NM_001378743.1	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461284 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726960

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	T;.;.;T;.;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.085	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.51	N;N;N;.;N;N;N
Sift	Benign	0.19	T;T;T;.;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;.
Vest4		0.18
MutPred		0.17		.;Gain of phosphorylation at G330 (P = 0.0198);.;.;.;Gain of phosphorylation at G330 (P = 0.0198);.;
MVP		0.36
MPC		0.40
ClinPred		0.33	T
GERP RS		5.1
Varity_R		0.072
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs587778226; hg19: chr16-50810155;