rs572309510

chr18-31093653-GA-Gchr18-31093653-GA-GAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_024422.6(DSC2):c.70-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,536,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DSC2 NM_024422.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.596

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-31093653-GA-G is Benign according to our data. Variant chr18-31093653-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 163194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31093653-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000605 (90/148772) while in subpopulation AFR AF= 0.00188 (76/40530). AF 95% confidence interval is 0.00154. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.70-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000280904.11
DSC2	NM_001406506.1	c.-360-11del		splice_polypyrimidine_tract_variant, intron_variant
DSC2	NM_001406507.1	c.-360-11del		splice_polypyrimidine_tract_variant, intron_variant
DSC2	NM_004949.5	c.70-11del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.70-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.70-11del		splice_polypyrimidine_tract_variant, intron_variant		1
DSC2	ENST00000648081.1	c.-397-11del		splice_polypyrimidine_tract_variant, intron_variant
DSC2	ENST00000682357.1	c.-360-11del		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 91 AN: 148670 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000467

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000595

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000344 AC: 82 AN: 238322 Hom.: 0 AF XY: 0.000301 AC XY: 39 AN XY: 129528

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.0000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.0000482

Gnomad NFE exome AF: 0.0000643

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000157 AC: 218 AN: 1388062 Hom.: 0 Cov.: 25 AF XY: 0.000158 AC XY: 109 AN XY: 690538

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.0000422

Gnomad4 EAS exome AF: 0.000108

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.0000637

Gnomad4 OTH exome AF: 0.000320

GnomAD4 genome AF: 0.000605 AC: 90 AN: 148772 Hom.: 0 Cov.: 32 AF XY: 0.000552 AC XY: 40 AN XY: 72484

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.000466

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000393

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000595

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000601

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 10, 2013	70-11delT in intron 1 of DSC2: This variant is not expected to have clinical sig nificance because it is located outside the conserved +/- 1, 2 region of the spl icing consensus sequence and as part of a polyT stretch. It does not alter the r egion of interest (ROI). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 05, 2019	Variant summary: DSC2 c.70-11delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 238322 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 96 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.70-11delT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2015	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. -

Arrhythmogenic right ventricular dysplasia 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs572309510; hg19: chr18-28673616;