18-31130596-C-A

Position:

• chr18-31130596-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 13/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.778

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]

DSCAS (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15975335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC1	NM_024421.2	c.2603G>T	p.Arg868Leu	missense_variant	16/16	ENST00000257198.6	NP_077739.1
DSC1	NM_004948.3	c.*126G>T		3_prime_UTR_variant	17/17		NP_004939.1
DSCAS	NR_110785.1	n.209-20203C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC1	ENST00000257198.6	c.2603G>T	p.Arg868Leu	missense_variant	16/16	2	NM_024421.2	ENSP00000257198.6
DSC1	ENST00000257197	c.*126G>T		3_prime_UTR_variant	17/17	1		ENSP00000257197.3
DSCAS	ENST00000654403.2	n.291C>A		non_coding_transcript_exon_variant	3/3
DSCAS	ENST00000581836.2	n.225-20203C>A		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.2603G>T (p.R868L) alteration is located in exon 16 (coding exon 16) of the DSC1 gene. This alteration results from a G to T substitution at nucleotide position 2603, causing the arginine (R) at amino acid position 868 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.096	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.27
Sift	Benign	0.41	T
Sift4G	Benign	0.17	T
Polyphen		0.82	P
Vest4		0.15
MutPred		0.40		Loss of disorder (P = 0.0649);
MVP		0.85
MPC		0.31
ClinPred		0.83	D
GERP RS		1.4
Varity_R		0.14
gMVP		0.20

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

Other links and lift over

dbSNP: rs1173352297; hg19: chr18-28710559;