rs2228474

Variant names:

• chr18-30996827-C-G
• rs2228474
• NM_001941.5:c.2457G>C

Your query was ambiguous. Multiple possible variants found:

• chr18-30996827-C-G
• chr18-30996827-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001941.5(DSC3):​c.2457G>C​(p.Ser819Ser) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S819S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC3 NM_001941.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.81
• Publications: 2 publications found

Genes affected

DSC3 (HGNC:3037): (desmocollin 3) 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. The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Mutations in this gene are a cause of hypotrichosis and recurrent skin vesicles disorder. The protein can act as an autoantigen in pemphigus diseases, and it is also considered to be a biomarker for some cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

DSC3 Gene-Disease associations (from GenCC):

• hereditary hypotrichosis with recurrent skin vesicles

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=-4.81 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC3	NM_001941.5	c.2457G>C	p.Ser819Ser	synonymous_variant	Exon 15 of 16	ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.2457G>C	p.Ser819Ser	synonymous_variant	Exon 15 of 17		NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.2457G>C	p.Ser819Ser	synonymous_variant	Exon 15 of 16	1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.2457G>C	p.Ser819Ser	synonymous_variant	Exon 15 of 17	5		ENSP00000392068.1
DSC3	ENST00000584980.1	c.579G>C	p.Ser193Ser	synonymous_variant	Exon 4 of 6	5		ENSP00000464283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 46

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.041
DANN	Benign	0.61
PhyloP100		-4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2228474; hg19: chr18-28576793;