16-50796443-C-G

Variant names:

• chr16-50796443-C-G
• rs121908390
• NM_001378743.1:c.2806C>G

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.2806C>G​(p.Arg936Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYLD NM_001378743.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 19 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, 0.889

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.2806C>G	p.Arg936Gly	missense	Exon 19 of 19	NP_001365672.1	Q9NQC7-1
	CYLD	NM_015247.3		c.2806C>G	p.Arg936Gly	missense	Exon 20 of 20	NP_056062.1	Q9NQC7-1
	CYLD	NM_001042355.2		c.2797C>G	p.Arg933Gly	missense	Exon 18 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.2806C>G	p.Arg936Gly	missense	Exon 19 of 19	ENSP00000392025.3	Q9NQC7-1
	CYLD	ENST00000398568.6	TSL:1	c.2797C>G	p.Arg933Gly	missense	Exon 18 of 18	ENSP00000381574.2	Q9NQC7-2
	CYLD	ENST00000569418.5	TSL:1	c.2797C>G	p.Arg933Gly	missense	Exon 18 of 18	ENSP00000457576.1	Q9NQC7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249312 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.6	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.83
Sift	Benign	0.063	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.65		Loss of MoRF binding (P = 0.0285)
MVP		0.98
MPC		2.5
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.74
gMVP		0.85

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: rs121908390; hg19: chr16-50830354;