Genetic Variant NM_001378743.1:c.2041G>C (chr16-50786946-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001378743.1(CYLD):c.2041G>C(p.Asp681His) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CYLD
NM_001378743.1 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.20

Publications

1 publications found

Variant links:

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 links:

CYLD-AS2 (HGNC:56848): (CYLD antisense RNA 2)

CYLD-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYLD	NM_001378743.1	MANE Select	c.2041G>C	p.Asp681His	missense splice_region	Exon 13 of 19	NP_001365672.1	Q9NQC7-1
CYLD	NM_015247.3		c.2041G>C	p.Asp681His	missense splice_region	Exon 14 of 20	NP_056062.1	Q9NQC7-1
CYLD	NM_001042355.2		c.2032G>C	p.Asp678His	missense splice_region	Exon 12 of 18	NP_001035814.1	Q9NQC7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYLD	ENST00000427738.8	TSL:5 MANE Select	c.2041G>C	p.Asp681His	missense splice_region	Exon 13 of 19	ENSP00000392025.3	Q9NQC7-1
CYLD	ENST00000398568.6	TSL:1	c.2032G>C	p.Asp678His	missense splice_region	Exon 12 of 18	ENSP00000381574.2	Q9NQC7-2
CYLD	ENST00000569418.5	TSL:1	c.2032G>C	p.Asp678His	missense splice_region	Exon 12 of 18	ENSP00000457576.1	Q9NQC7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cylindromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.5

PhyloP100

9.2

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.84

Vest4

0.92

MutPred

0.66

Gain of helix (P = 0.062)

MVP

0.99

MPC

2.3

ClinPred

0.99

GERP RS

5.5

Varity_R

0.83

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over