rs1893962

Variant names:

• chr18-31069200-A-G
• rs1893962
• NM_024422.6:c.2251-49T>C

Variant summary

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

The NM_024422.6(DSC2):​c.2251-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,611,092 control chromosomes in the GnomAD database, including 3,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (284 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2876 hom.)
• Consequence: DSC2 NM_024422.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0300

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-31069200-A-G is Benign according to our data. Variant chr18-31069200-A-G is described in ClinVar as [Benign]. Clinvar id is 261707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31069200-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2251-49T>C		intron_variant	Intron 14 of 15	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2251-49T>C		intron_variant	Intron 14 of 16		NP_004940.1
DSC2	NM_001406506.1	c.1822-49T>C		intron_variant	Intron 14 of 15		NP_001393435.1
DSC2	NM_001406507.1	c.1822-49T>C		intron_variant	Intron 14 of 16		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2251-49T>C		intron_variant	Intron 14 of 15	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2251-49T>C		intron_variant	Intron 14 of 16	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1822-49T>C		intron_variant	Intron 15 of 16			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1822-49T>C		intron_variant	Intron 14 of 15			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.0532 AC: 8099 AN: 152156 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.0380

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0468

GnomAD3 exomes AF: 0.0668 AC: 16334 AN: 244476 Hom.: 784 AF XY: 0.0622 AC XY: 8272 AN XY: 133052

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0994

Gnomad SAS exome AF: 0.0411

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0544

Gnomad OTH exome AF: 0.0523

GnomAD4 exome AF: 0.0589 AC: 85875 AN: 1458818 Hom.: 2876 Cov.: 31 AF XY: 0.0575 AC XY: 41752 AN XY: 725790

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.0926

Gnomad4 SAS exome AF: 0.0397

Gnomad4 FIN exome AF: 0.0349

Gnomad4 NFE exome AF: 0.0577

Gnomad4 OTH exome AF: 0.0556

GnomAD4 genome AF: 0.0534 AC: 8135 AN: 152274 Hom.: 284 Cov.: 32 AF XY: 0.0540 AC XY: 4023 AN XY: 74454

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.0934

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.0948

Gnomad4 SAS AF: 0.0446

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0547

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0540 Hom.: 84

Bravo AF: 0.0580

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.46

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: rs1893962; hg19: chr18-28649166;