16-50749939-G-A

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.241G>A(p.Val81Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V81F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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=0.14082506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYLD	NM_001378743.1	c.241G>A	p.Val81Ile	missense_variant	3/19	ENST00000427738.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYLD	ENST00000427738.8	c.241G>A	p.Val81Ile	missense_variant	3/19	5	NM_001378743.1	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

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

Nov 27, 2023

The c.241G>A (p.V81I) alteration is located in exon 4 (coding exon 1) of the CYLD gene. This alteration results from a G to A substitution at nucleotide position 241, causing the valine (V) at amino acid position 81 to be replaced by an isoleucine (I). 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	0.061
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;T;.;T;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T;.;.;T;T;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.40	N;N;N;N;.;N;N;N;N
Sift	Benign	0.45	T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		0.0060, 0.0040	.;B;B;B;.;.;B;B;.
Vest4		0.095, 0.090, 0.10, 0.10, 0.099, 0.092, 0.091
MutPred		0.25		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP		0.54
MPC		0.33
ClinPred		0.25	T
GERP RS		6.2
Varity_R		0.042
gMVP		0.14

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: rs916449502; hg19: chr16-50783850;