16-50749939-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001378743.1(CYLD):c.241G>T(p.Val81Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V81I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• 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 2 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=0.34430927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYLD	NM_001378743.1	c.241G>T	p.Val81Phe	missense_variant	3/19	ENST00000427738.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYLD	ENST00000427738.8	c.241G>T	p.Val81Phe	missense_variant	3/19	5	NM_001378743.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248784 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.085	T;.;T;.;T;.;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T;.;.;T;T;.;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;N;N;N;.;N;N;N;N
Sift	Uncertain	0.013	D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D;D;D
Polyphen		0.88, 0.81	.;P;P;P;.;.;P;P;.
Vest4		0.34, 0.35, 0.61, 0.34, 0.35, 0.34
MutPred		0.33		Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.98
MPC		0.53
ClinPred		0.33	T
GERP RS		6.2
Varity_R		0.35
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;