NM_001378743.1:c.1919T>C

Variant names:

• chr16-50784421-T-C
• NM_001378743.1:c.1919T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378743.1(CYLD):​c.1919T>C​(p.Leu640Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L640L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32
• 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-AS2 (HGNC:56848): (CYLD antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

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.1919T>C	p.Leu640Pro	missense	Exon 12 of 19	NP_001365672.1	Q9NQC7-1
	CYLD	NM_015247.3		c.1919T>C	p.Leu640Pro	missense	Exon 13 of 20	NP_056062.1	Q9NQC7-1
	CYLD	NM_001042355.2		c.1910T>C	p.Leu637Pro	missense	Exon 11 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.1919T>C	p.Leu640Pro	missense	Exon 12 of 19	ENSP00000392025.3	Q9NQC7-1
	CYLD	ENST00000398568.6	TSL:1	c.1910T>C	p.Leu637Pro	missense	Exon 11 of 18	ENSP00000381574.2	Q9NQC7-2
	CYLD	ENST00000569418.5	TSL:1	c.1910T>C	p.Leu637Pro	missense	Exon 11 of 18	ENSP00000457576.1	Q9NQC7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.65		Loss of stability (P = 0.0063)
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.99

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: chr16-50818332;