Genetic Variant DSC1:p.Arg868Leu (chr18-31130596-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024421.2(DSC1):c.2603G>T(p.Arg868Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DSC1
NM_024421.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.778

Publications

2 publications found

Variant links:

Genes affected

DSC1 (HGNC:3035): (desmocollin 1) The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. A subtype of IgA pemphigus, a life-threatening autoimmune disease, is characterized by the presence of autoantibodies that target the encoded protein. The desmosomal family members are arranged in two clusters on chromosome 18. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protein. [provided by RefSeq, Nov 2015]

DSC1 links:

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

DSCAS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15975335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024421.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSC1	NM_024421.2	MANE Select	c.2603G>T	p.Arg868Leu	missense	Exon 16 of 16	NP_077739.1	Q08554-1
DSC1	NM_004948.3		c.*126G>T		3_prime_UTR	Exon 17 of 17	NP_004939.1	Q08554-2
DSCAS	NR_110785.1		n.209-20203C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSC1	ENST00000257198.6	TSL:2 MANE Select	c.2603G>T	p.Arg868Leu	missense	Exon 16 of 16	ENSP00000257198.6	Q08554-1
DSC1	ENST00000257197.7	TSL:1	c.*126G>T		3_prime_UTR	Exon 17 of 17	ENSP00000257197.3	Q08554-2
DSCAS	ENST00000654403.3		n.291C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.096

M_CAP

Benign

0.043

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.0

PhyloP100

0.78

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Benign

0.41

Sift4G

Benign

0.17

Polyphen

0.82

Vest4

0.15

MutPred

0.40

Loss of disorder (P = 0.0649)

MVP

0.85

MPC

0.31

ClinPred

0.83

GERP RS

1.4

Varity_R

0.14

gMVP

0.20

Mutation Taster

=94/6

polymorphism

(source)

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

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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