chr18-31087695-AAAGTAT-A

Position:

• chr18-31087695-AAAGTAT-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_024422.6(DSC2):​c.743_748delATACTT​(p.Tyr248_Thr249del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: DSC2 NM_024422.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.05

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_024422.6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.743_748delATACTT	p.Tyr248_Thr249del	disruptive_inframe_deletion	6/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.743_748delATACTT	p.Tyr248_Thr249del	disruptive_inframe_deletion	6/17		NP_004940.1
DSC2	NM_001406506.1	c.314_319delATACTT	p.Tyr105_Thr106del	disruptive_inframe_deletion	6/16		NP_001393435.1
DSC2	NM_001406507.1	c.314_319delATACTT	p.Tyr105_Thr106del	disruptive_inframe_deletion	6/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.743_748delATACTT	p.Tyr248_Thr249del	disruptive_inframe_deletion	6/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.743_748delATACTT	p.Tyr248_Thr249del	disruptive_inframe_deletion	6/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.314_319delATACTT	p.Tyr105_Thr106del	disruptive_inframe_deletion	7/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.314_319delATACTT	p.Tyr105_Thr106del	disruptive_inframe_deletion	6/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250810 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135626

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2021	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.743_748del, results in the deletion of 2 amino acid(s) of the DSC2 protein (p.Tyr248_Thr249del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with DSC2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 228626). -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 06, 2021	The c.743_748del variant identified in the DSC2 gene is predicted to result in deletion of two amino acids (p.(Tyr248_Thr249del)) that are located in the extracellular Cadherin 2 domain of the encoded protein without causing a shift in the reading frame (in-frame deletion). This variant is observed in three individuals across population databases (gnomAD v2.1.1 and v3.1.1, TOPMed Freeze 5) suggesting it is not a common benign variant in the populations represented in those databases. This variant has not been reported in the literature before, however, it has been reported three times in ClinVar as Variant of Uncertain Significance(ClinVar ID: 228626). Additionally, this variant was reported to be found in trans with the p.(Phe250Ser) variant in an individual with Arrhythmogenic right ventriculardysplasia 11 (ClinVar ID: 523128). Two single nucleotide variants and one deletion-insertion variant that are predicted to result in a missense variation at the residue p.Thr249 have also been reported six times in ClinVar as Variants of Unknown Significance (ClinVar IDs: 199763, 920996, 960002). In silico predictions are not applicable to this variant. Based on the available evidence the c.743_748del (p.(Tyr248_Thr249del)) variant identified in the DSC2 gene is reported as Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 02, 2015

The p.Tyr248_Thr249del variant in DSC2 has not been previously reported in indiv iduals with cardiomyopathy and data from large population studies is insufficien t to assess the frequency of this variant. This variant is a deletion of 2 amino acids starting at position 248 and is not predicted to alter the protein readin g-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Tyr248_Thr249del variant is uncertain. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2018

The c.743_748delATACTT variant of uncertain significance in the DSC2 gene has not been published as pathogenic or been reported as benign to our knowledge. The c.743_748delATACTT variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant results in an in-frame deletion of two amino acids (tyrosine and threonine) at codons 248 and 249, denoted p.Tyr248_Thr249del, and does not result in a shift in reading frame or a premature stop codon. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, two other in-frame deletions in the DSC2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Nevertheless, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. -

DSC2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

The DSC2 c.743_748del6 variant is predicted to result in an in-frame deletion (p.Tyr248_Thr249del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

This variant causes an in-frame deletion of two amino acids (p.Tyr248_Thr249del) in the DSC2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 1/250810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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: rs776784065; hg19: chr18-28667658;