rs397517401

Positions:

• chr18-31089428-TTAG-TAA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_024422.6(DSC2):​c.630+8_630+10delinsTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-31089429-TAG-AA is Benign according to our data. Variant chr18-31089429-TAG-AA is described in ClinVar as [Likely_benign]. Clinvar id is 46193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.630+8_630+10delinsTT		splice_region_variant, intron_variant		ENST00000280904.11	NP_077740.1
DSC2	NM_001406506.1	c.201+8_201+10delinsTT		splice_region_variant, intron_variant			NP_001393435.1
DSC2	NM_001406507.1	c.201+8_201+10delinsTT		splice_region_variant, intron_variant			NP_001393436.1
DSC2	NM_004949.5	c.630+8_630+10delinsTT		splice_region_variant, intron_variant			NP_004940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.630+8_630+10delinsTT		splice_region_variant, intron_variant		1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.630+8_630+10delinsTT		splice_region_variant, intron_variant		1		ENSP00000251081
DSC2	ENST00000648081.1	c.201+8_201+10delinsTT		splice_region_variant, intron_variant				ENSP00000497441
DSC2	ENST00000682357.1	c.201+8_201+10delinsTT		splice_region_variant, intron_variant				ENSP00000507826

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2012	630+8_630+10delinsTT in intron 5 of DSC2: This variant is not expected to have c linical significance because it is not located within the splice consensus seque nce. 630+8_630+10delinsTT in intron 5 of DSC2 (allele frequency = n/a) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517401; hg19: chr18-28669392;