rs587778223

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-50784435-G-A
• chr16-50784435-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001378743.1(CYLD):​c.1933G>A​(p.Val645Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,612,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.15
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 66 AD gene.

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>A	p.Val645Ile	missense	Exon 12 of 19	NP_001365672.1
	CYLD	NM_015247.3		c.1933G>A	p.Val645Ile	missense	Exon 13 of 20	NP_056062.1
	CYLD	NM_001042355.2		c.1924G>A	p.Val642Ile	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>A	p.Val645Ile	missense	Exon 12 of 19	ENSP00000392025.3
	CYLD	ENST00000398568.6	TSL:1	c.1924G>A	p.Val642Ile	missense	Exon 11 of 18	ENSP00000381574.2
	CYLD	ENST00000569418.5	TSL:1	c.1924G>A	p.Val642Ile	missense	Exon 11 of 18	ENSP00000457576.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 248848 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 726732

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.000112 AC: 5 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: 0.0000116 AC: 1 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: 0.0000504 AC: 56 AN: 1111710

Other (OTH) AF: 0.0000497 AC: 3 AN: 60356

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.52
Sift	Benign	0.046	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.56		Loss of loop (P = 0.0512)
MVP		0.76
MPC		2.0
ClinPred		0.42	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.76
Mutation Taster		=65/35	polymorphism

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;