18-30994591-T-G

Position:

• chr18-30994591-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001941.5(DSC3):​c.2494-219A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 977,306 control chromosomes in the GnomAD database, including 1,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (141 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1016 hom.)
• Consequence: DSC3 NM_001941.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0370

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-30994591-T-G is Benign according to our data. Variant chr18-30994591-T-G is described in ClinVar as [Benign]. Clinvar id is 1266158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC3	NM_001941.5	c.2494-219A>C		intron_variant		ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.2494-95A>C		intron_variant			NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.2494-219A>C		intron_variant		1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.2494-95A>C		intron_variant		5		ENSP00000392068.1
DSC3	ENST00000584980.1	c.616-95A>C		intron_variant		5		ENSP00000464283.1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4876 AN: 152118 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0494

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0449 AC: 37071 AN: 825070 Hom.: 1016 AF XY: 0.0454 AC XY: 19520 AN XY: 430014

Gnomad4 AFR exome AF: 0.00594

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.0563

Gnomad4 FIN exome AF: 0.0635

Gnomad4 NFE exome AF: 0.0473

Gnomad4 OTH exome AF: 0.0431

GnomAD4 genome AF: 0.0320 AC: 4871 AN: 152236 Hom.: 141 Cov.: 32 AF XY: 0.0338 AC XY: 2518 AN XY: 74434

Gnomad4 AFR AF: 0.00724

Gnomad4 AMR AF: 0.0255

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0499

Gnomad4 FIN AF: 0.0633

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.0470 Hom.: 36

Bravo AF: 0.0263

Asia WGS AF: 0.0160 AC: 57 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.73

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: rs1472222; hg19: chr18-28574557;