16-50784435-G-T

Variant names:

• chr16-50784435-G-T
• NM_001378743.1:c.1933G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378743.1(CYLD):​c.1933G>T​(p.Val645Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.15

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]

ENSG00000260616 (HGNC:56848): (CYLD antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.1933G>T	p.Val645Phe	missense_variant	Exon 12 of 19	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.1933G>T	p.Val645Phe	missense_variant	Exon 12 of 19	5	NM_001378743.1	ENSP00000392025.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726732

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T;.;T;.;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;.;D;.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.5	.;M;.;.;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D;D;D;.;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;.
Vest4		0.96
MutPred		0.58		.;Gain of helix (P = 0.0425);.;.;.;Gain of helix (P = 0.0425);.;
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.98

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: chr16-50818346;