rs200494719

Variant names:

• chr16-50779818-G-A
• rs200494719
• NM_001378743.1:c.1292G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378743.1(CYLD):​c.1292G>A​(p.Gly431Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000425 in 1,613,352 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (9 hom.)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 6.10
• 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 Gene-Disease associations (from GenCC):

• Brooke-Spiegler syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial cylindromatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
• frontotemporal dementia and/or amyotrophic lateral sclerosis 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• trichoepithelioma, multiple familial, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial multiple trichoepithelioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057254434).
• BP6: Variant 16-50779818-G-A is Benign according to our data. Variant chr16-50779818-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000237 (36/151584) while in subpopulation SAS AF = 0.00749 (36/4804). AF 95% confidence interval is 0.00556. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	NM_001378743.1	MANE Select	c.1292G>A	p.Gly431Glu	missense	Exon 9 of 19	NP_001365672.1
	CYLD	NM_015247.3		c.1292G>A	p.Gly431Glu	missense	Exon 10 of 20	NP_056062.1
	CYLD	NM_001042355.2		c.1283G>A	p.Gly428Glu	missense	Exon 8 of 18	NP_001035814.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	ENST00000427738.8	TSL:5 MANE Select	c.1292G>A	p.Gly431Glu	missense	Exon 9 of 19	ENSP00000392025.3
	CYLD	ENST00000398568.6	TSL:1	c.1283G>A	p.Gly428Glu	missense	Exon 8 of 18	ENSP00000381574.2
	CYLD	ENST00000569418.5	TSL:1	c.1283G>A	p.Gly428Glu	missense	Exon 8 of 18	ENSP00000457576.1

Frequencies

GnomAD3 genomes AF: 0.000238 AC: 36 AN: 151464 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: 0.00749

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000903 AC: 225 AN: 249278 AF XY: 0.00133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000444 AC: 649 AN: 1461768 Hom.: 9 Cov.: 32 AF XY: 0.000668 AC XY: 486 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00721 AC: 622 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000237 AC: 36 AN: 151584 Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 30 AN XY: 74008

African (AFR) AF: 0.00 AC: 0 AN: 41322

American (AMR) AF: 0.00 AC: 0 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00749 AC: 36 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00100 AC: 121

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brooke-Spiegler syndrome (1)
-	-	1	Familial cylindromatosis (1)
-	-	1	Familial multiple trichoepitheliomata (1)
-	-	1	Trichoepithelioma, multiple familial, 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0057	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.90	L
PhyloP100		6.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.13	N
REVEL	Uncertain	0.44
Sift	Benign	0.037	D
Sift4G	Benign	0.29	T
Polyphen		0.96	D
Vest4		0.25
MVP		0.77
MPC		1.1
ClinPred		0.042	T
GERP RS		5.6
Varity_R		0.23
gMVP		0.40
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200494719; hg19: chr16-50813729; COSMIC: COSV61094636;