16-50749517-A-G

Variant names:

• chr16-50749517-A-G
• rs7187352
• NM_001378743.1:c.-123-59A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378743.1(CYLD):​c.-123-59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 622,130 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (675 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (236 hom.)
• Consequence: CYLD NM_001378743.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.59
• Publications: 2 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 (BayesDel_noAF=-0.57).
• BP6: Variant 16-50749517-A-G is Benign according to our data. Variant chr16-50749517-A-G is described in ClinVar as Benign. ClinVar VariationId is 1280234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

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.-123-59A>G		intron	N/A	NP_001365672.1	Q9NQC7-1
	CYLD	NM_015247.3		c.-123-59A>G		intron	N/A	NP_056062.1	Q9NQC7-1
	CYLD	NM_001042355.2		c.-123-59A>G		intron	N/A	NP_001035814.1	Q9NQC7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	ENST00000427738.8	TSL:5 MANE Select	c.-123-59A>G		intron	N/A	ENSP00000392025.3	Q9NQC7-1
	CYLD	ENST00000398568.6	TSL:1	c.-123-59A>G		intron	N/A	ENSP00000381574.2	Q9NQC7-2
	CYLD	ENST00000569418.5	TSL:1	c.-123-59A>G		intron	N/A	ENSP00000457576.1	Q9NQC7-2

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7963 AN: 152166 Hom.: 671 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.00786 AC: 3695 AN: 469846 Hom.: 236 Cov.: 5 AF XY: 0.00680 AC XY: 1682 AN XY: 247342

African (AFR) AF: 0.182 AC: 2320 AN: 12766

American (AMR) AF: 0.0136 AC: 242 AN: 17840

Ashkenazi Jewish (ASJ) AF: 0.00366 AC: 51 AN: 13920

East Asian (EAS) AF: 0.00 AC: 0 AN: 31404

South Asian (SAS) AF: 0.000767 AC: 34 AN: 44342

European-Finnish (FIN) AF: 0.0000675 AC: 2 AN: 29620

Middle Eastern (MID) AF: 0.0162 AC: 33 AN: 2040

European-Non Finnish (NFE) AF: 0.00205 AC: 597 AN: 291130

Other (OTH) AF: 0.0155 AC: 416 AN: 26784

GnomAD4 genome AF: 0.0525 AC: 7994 AN: 152284 Hom.: 675 Cov.: 32 AF XY: 0.0499 AC XY: 3717 AN XY: 74464

African (AFR) AF: 0.181 AC: 7511 AN: 41544

American (AMR) AF: 0.0168 AC: 257 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68024

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0206 Hom.: 90

Bravo AF: 0.0614

Asia WGS AF: 0.0120 AC: 41 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		1.6
PromoterAI		-0.0095	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs7187352; hg19: chr16-50783428;