NM_001378743.1:c.2469+26A>G

Variant names:

• chr16-50793690-A-G
• rs2302759
• NM_001378743.1:c.2469+26A>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.2469+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,409,174 control chromosomes in the GnomAD database, including 456,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54367 hom., cov: 32)
  • Exomes 𝑓: 0.80 (401928 hom.)
• Consequence: CYLD NM_001378743.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.454
• Publications: 24 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-50793690-A-G is Benign according to our data. Variant chr16-50793690-A-G is described in ClinVar as Benign. ClinVar VariationId is 1244811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	NM_001378743.1	MANE Select	c.2469+26A>G		intron	N/A	NP_001365672.1
	CYLD	NM_015247.3		c.2469+26A>G		intron	N/A	NP_056062.1
	CYLD	NM_001042355.2		c.2460+26A>G		intron	N/A	NP_001035814.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	ENST00000427738.8	TSL:5 MANE Select	c.2469+26A>G		intron	N/A	ENSP00000392025.3
	CYLD	ENST00000398568.6	TSL:1	c.2460+26A>G		intron	N/A	ENSP00000381574.2
	CYLD	ENST00000569418.5	TSL:1	c.2460+26A>G		intron	N/A	ENSP00000457576.1

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127934 AN: 152094 Hom.: 54309 Cov.: 32

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.894

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.849

GnomAD2 exomes AF: 0.789 AC: 196618 AN: 249294 AF XY: 0.785

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.759

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.753

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.797 AC: 1002363 AN: 1256960 Hom.: 401928 Cov.: 18 AF XY: 0.794 AC XY: 505398 AN XY: 636298

African (AFR) AF: 0.966 AC: 28513 AN: 29510

American (AMR) AF: 0.767 AC: 34082 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 22816 AN: 24824

East Asian (EAS) AF: 0.736 AC: 28541 AN: 38760

South Asian (SAS) AF: 0.685 AC: 56205 AN: 82094

European-Finnish (FIN) AF: 0.751 AC: 40031 AN: 53286

Middle Eastern (MID) AF: 0.876 AC: 4731 AN: 5400

European-Non Finnish (NFE) AF: 0.805 AC: 744381 AN: 925140

Other (OTH) AF: 0.805 AC: 43063 AN: 53482

GnomAD4 genome AF: 0.841 AC: 128049 AN: 152214 Hom.: 54367 Cov.: 32 AF XY: 0.836 AC XY: 62174 AN XY: 74406

African (AFR) AF: 0.959 AC: 39819 AN: 41532

American (AMR) AF: 0.809 AC: 12371 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3179 AN: 3470

East Asian (EAS) AF: 0.700 AC: 3627 AN: 5184

South Asian (SAS) AF: 0.675 AC: 3258 AN: 4824

European-Finnish (FIN) AF: 0.765 AC: 8096 AN: 10586

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.806 AC: 54830 AN: 68012

Other (OTH) AF: 0.848 AC: 1790 AN: 2110

Alfa AF: 0.824 Hom.: 117054

Bravo AF: 0.854

Asia WGS AF: 0.681 AC: 2371 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Familial cylindromatosis Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Trichoepithelioma, multiple familial, 1 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Brooke-Spiegler syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.43
PhyloP100		-0.45
PromoterAI		-0.010	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: rs2302759; hg19: chr16-50827601; COSMIC: COSV61092657; COSMIC: COSV61092657;