16-50749722-A-C

Variant names:

• chr16-50749722-A-C
• NM_001378743.1:c.24A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378743.1(CYLD):​c.24A>C​(p.Gln8His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• 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 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.24A>C	p.Gln8His	missense	Exon 3 of 19	NP_001365672.1	Q9NQC7-1
	CYLD	NM_015247.3		c.24A>C	p.Gln8His	missense	Exon 4 of 20	NP_056062.1	Q9NQC7-1
	CYLD	NM_001042355.2		c.24A>C	p.Gln8His	missense	Exon 3 of 18	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.24A>C	p.Gln8His	missense	Exon 3 of 19	ENSP00000392025.3	Q9NQC7-1
	CYLD	ENST00000398568.6	TSL:1	c.24A>C	p.Gln8His	missense	Exon 3 of 18	ENSP00000381574.2	Q9NQC7-2
	CYLD	ENST00000569418.5	TSL:1	c.24A>C	p.Gln8His	missense	Exon 3 of 18	ENSP00000457576.1	Q9NQC7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.0	L
PhyloP100		7.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.18		Gain of glycosylation at S3 (P = 0.073)
MVP		0.97
MPC		1.2
ClinPred		0.96	D
GERP RS		4.6
PromoterAI		-0.044	Neutral
Varity_R		0.40
gMVP		0.66

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

hg19: chr16-50783633;