NM_001378743.1:c.125C>G

Variant names:

• chr16-50749823-C-G
• NM_001378743.1:c.125C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001378743.1(CYLD):​c.125C>G​(p.Pro42Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 5.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYLD	NM_001378743.1	c.125C>G	p.Pro42Arg	missense_variant	Exon 3 of 19	ENST00000427738.8	NP_001365672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYLD	ENST00000427738.8	c.125C>G	p.Pro42Arg	missense_variant	Exon 3 of 19	5	NM_001378743.1	ENSP00000392025.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;.;T;.;T;.;.;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;.;.;D;D;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	0.97	.;L;L;L;.;.;L;L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.070	T;D;D;D;.;T;D;D;D
Sift4G	Benign	0.099	T;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;D;D;.
Vest4		0.68, 0.73, 0.79, 0.68, 0.71, 0.73, 0.72
MutPred		0.32		Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);
MVP		0.92
MPC		1.2
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.47
gMVP		0.51

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-50783734;