18-31130528-A-T

Position:

chr18-31130528-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024421.2(DSC1):c.2671T>A(p.Cys891Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

DSC1
NM_024421.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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:):

DSCAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC1	NM_024421.2 linkuse as main transcript	c.2671T>A	p.Cys891Ser	missense_variant	16/16	ENST00000257198.6	NP_077739.1	Q08554-1
DSC1	NM_004948.3 linkuse as main transcript	c.*194T>A		3_prime_UTR_variant	17/17		NP_004939.1	Q08554-2Q9HB00
DSCAS	NR_110785.1 linkuse as main transcript	n.209-20271A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSC1	ENST00000257198.6 linkuse as main transcript	c.2671T>A	p.Cys891Ser	missense_variant	16/16	2	NM_024421.2	ENSP00000257198.6	Q08554-1
DSC1	ENST00000257197 linkuse as main transcript	c.*194T>A		3_prime_UTR_variant	17/17	1		ENSP00000257197.3	Q08554-2
DSCAS	ENST00000581836.2 linkuse as main transcript	n.225-20271A>T		intron_variant		4
DSCAS	ENST00000654403.2 linkuse as main transcript	n.257-34A>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251336

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2023

The c.2671T>A (p.C891S) alteration is located in exon 16 (coding exon 16) of the DSC1 gene. This alteration results from a T to A substitution at nucleotide position 2671, causing the cysteine (C) at amino acid position 891 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.68

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.51

Gain of disorder (P = 0.0165);

MVP

0.95

MPC

0.19

ClinPred

0.77

GERP RS

4.8

Varity_R

0.76

gMVP

0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over