16-50784435-G-T

Variant names:

• chr16-50784435-G-T
• rs587778223
• NM_001378743.1:c.1933G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V645I) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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]

CYLD-AS2 (HGNC:56848): (CYLD antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378743.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	NM_001378743.1	MANE Select	c.1933G>T	p.Val645Phe	missense	Exon 12 of 19	NP_001365672.1
	CYLD	NM_015247.3		c.1933G>T	p.Val645Phe	missense	Exon 13 of 20	NP_056062.1
	CYLD	NM_001042355.2		c.1924G>T	p.Val642Phe	missense	Exon 11 of 18	NP_001035814.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	ENST00000427738.8	TSL:5 MANE Select	c.1933G>T	p.Val645Phe	missense	Exon 12 of 19	ENSP00000392025.3
	CYLD	ENST00000398568.6	TSL:1	c.1924G>T	p.Val642Phe	missense	Exon 11 of 18	ENSP00000381574.2
	CYLD	ENST00000569418.5	TSL:1	c.1924G>T	p.Val642Phe	missense	Exon 11 of 18	ENSP00000457576.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111710

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.58		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

Other links and lift over

dbSNP: rs587778223; hg19: chr16-50818346;