chr18-31132656-T-C

Variant names:

Variant summary

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

The NM_024421.2(DSC1):c.2150A>G(p.Lys717Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSC1
NM_024421.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15

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:

ENSG00000263698 (HGNC:):

ENSG00000263698 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
DSC1	NM_024421.2 link	c.2150A>G	p.Lys717Arg	missense_variant	Exon 14 of 16	ENST00000257198.6	NP_077739.1	Q08554-1
DSC1	NM_004948.3 link	c.2150A>G	p.Lys717Arg	missense_variant	Exon 14 of 17		NP_004939.1	Q08554-2Q9HB00
DSCAS	NR_110785.1 link	n.209-18143T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSC1	ENST00000257198.6 link	c.2150A>G	p.Lys717Arg	missense_variant	Exon 14 of 16	2	NM_024421.2	ENSP00000257198.6	Q08554-1
DSC1	ENST00000257197.7 link	c.2150A>G	p.Lys717Arg	missense_variant	Exon 14 of 17	1		ENSP00000257197.3	Q08554-2
DSCAS	ENST00000581836.2 link	n.225-18143T>C		intron_variant	Intron 2 of 3	4
ENSG00000263698	ENST00000582307.1 link	n.*162T>C		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250930

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135642

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461108

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726846

show subpopulations

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:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2150A>G (p.K717R) alteration is located in exon 14 (coding exon 14) of the DSC1 gene. This alteration results from a A to G substitution at nucleotide position 2150, causing the lysine (K) at amino acid position 717 to be replaced by an arginine (R). 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

Benign

0.080

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

.;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.056

Sift

Benign

0.49

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.56

.;P

Vest4

0.23

MVP

0.75

MPC

0.23

ClinPred

0.28

GERP RS

4.7

Varity_R

0.078

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: -1

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