rs139399951

Positions:

• chr18-31082930-G-A
• chr18-31082930-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024422.6(DSC2):​c.1073C>T​(p.Thr358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,162 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.752

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 (MetaRNN=0.009298474).
• BP6: Variant 18-31082930-G-A is Benign according to our data. Variant chr18-31082930-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31082930-G-A is described in Lovd as [Benign]. Variant chr18-31082930-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000985 (150/152326) while in subpopulation AMR AF= 0.00209 (32/15298). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1073C>T	p.Thr358Ile	missense_variant	8/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1073C>T	p.Thr358Ile	missense_variant	8/17		NP_004940.1
DSC2	NM_001406506.1	c.644C>T	p.Thr215Ile	missense_variant	8/16		NP_001393435.1
DSC2	NM_001406507.1	c.644C>T	p.Thr215Ile	missense_variant	8/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1073C>T	p.Thr358Ile	missense_variant	8/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1073C>T	p.Thr358Ile	missense_variant	8/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.644C>T	p.Thr215Ile	missense_variant	9/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.644C>T	p.Thr215Ile	missense_variant	8/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00133 AC: 335 AN: 250956 Hom.: 3 AF XY: 0.00131 AC XY: 178 AN XY: 135662

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00119 AC: 1738 AN: 1460836 Hom.: 4 Cov.: 31 AF XY: 0.00119 AC XY: 862 AN XY: 726772

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00412

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.000962

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00115 AC XY: 86 AN XY: 74490

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000895

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 28, 2022	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2017	p.Thr358Ile in exon 8 of DSC2: This variant is not expected to have clinical sig nificance because it has been identified in 0.37% (94/25778) of Finnish chromoso mes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http:/ /gnomAD.broadinstitute.org; dbSNP rs139399951). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2020	Variant summary: DSC2 c.1073C>T (p.Thr358Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250956 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 8-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 benign. c.1073C>T has been reported in the literature in an individual with a possible diagnosis of arrhythmogenic cardiomyopathy (AC), however, two first-degree relatives carrying the variant, were unaffected, and there was no family history of AC (Rasmussen_2014). These authors also reported that patient derived keratinocytes expressed normal amount of the DSC2 protein, however, this does not allow conclusions about the variant effect on protein function (Rasmussen_2014). 12 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 24704780, 18678517, 25351510, 27153395) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -

Cardiac arrest Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 26, 2014

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Dec 01, 2015

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial isolated arrhythmogenic right ventricular dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Benign	0.057
Sift	Benign	0.056	T;D;.
Sift4G	Benign	0.17	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.13
MVP		0.54
MPC		0.080
ClinPred		0.048	T
GERP RS		1.4
Varity_R		0.097
gMVP		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: rs139399951; hg19: chr18-28662896;