rs786205360

Positions:

• chr18-31069031-GTCC-G
• chr18-31069031-G-GTCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_024422.6(DSC2):​c.2368_2370delGGA​(p.Gly790del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,614,076 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (7 hom.)
• Consequence: DSC2 NM_024422.6 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:12
• Conservation: PhyloP100: 2.93

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_024422.6. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 18-31069031-GTCC-G is Benign according to our data. Variant chr18-31069031-GTCC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180319.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=8}. Variant chr18-31069031-GTCC-G is described in Lovd as [Benign]. Variant chr18-31069031-GTCC-G is described in Lovd as [Likely_benign]. Variant chr18-31069031-GTCC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000762 (116/152230) while in subpopulation EAS AF= 0.0206 (106/5158). AF 95% confidence interval is 0.0174. There are 2 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2368_2370delGGA	p.Gly790del	conservative_inframe_deletion	15/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2368_2370delGGA	p.Gly790del	conservative_inframe_deletion	15/17		NP_004940.1
DSC2	NM_001406506.1	c.1939_1941delGGA	p.Gly647del	conservative_inframe_deletion	15/16		NP_001393435.1
DSC2	NM_001406507.1	c.1939_1941delGGA	p.Gly647del	conservative_inframe_deletion	15/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2368_2370delGGA	p.Gly790del	conservative_inframe_deletion	15/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2368_2370delGGA	p.Gly790del	conservative_inframe_deletion	15/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1939_1941delGGA	p.Gly647del	conservative_inframe_deletion	16/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1939_1941delGGA	p.Gly647del	conservative_inframe_deletion	15/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152112 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0205

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00139 AC: 348 AN: 251120 Hom.: 5 AF XY: 0.00122 AC XY: 166 AN XY: 135710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0174

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000429 AC: 627 AN: 1461846 Hom.: 7 AF XY: 0.000422 AC XY: 307 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152230 Hom.: 2 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0206

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000756

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2015	p.Gly790del in exon 15 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 1.8% (153/8642) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs377272752). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2019	Variant summary: DSC2 c.2368_2370delGGA (p.Gly790del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0013 in 276824 control chromosomes, predominantly at a frequency of 0.018 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 110 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2368_2370delGGA has been reported in the literature in affected individuals, where in several reports the affected patients were of East Asian origin (e.g. Hata_2017, Ichikawa_2016, Gerhardt_2015, Ng_2013, Fressart_2010). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar submissions from four clinical diagnostic laboratories and one research laboratory (evaluation after 2014) cite the variant as benign (4x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -

Arrhythmogenic right ventricular dysplasia 11 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 12, 2018	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 17, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2013

There is insufficient or conflicting evidence for classification of this alteration. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 08, 2018

- -

Familial isolated arrhythmogenic right ventricular dysplasia Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 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: rs377272752; hg19: chr18-28648997;