chr18-31069076-T-C

Position:

• chr18-31069076-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024422.6(DSC2):​c.2326A>G​(p.Ile776Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,930 control chromosomes in the GnomAD database, including 12,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I776M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3924 hom., cov: 32)
  • Exomes 𝑓: 0.096 (8875 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.0600

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=3.502965E-4).
• BP6: Variant 18-31069076-T-C is Benign according to our data. Variant chr18-31069076-T-C is described in ClinVar as [Benign]. Clinvar id is 46178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31069076-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2326A>G	p.Ile776Val	missense_variant	15/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2326A>G	p.Ile776Val	missense_variant	15/17		NP_004940.1
DSC2	NM_001406506.1	c.1897A>G	p.Ile633Val	missense_variant	15/16		NP_001393435.1
DSC2	NM_001406507.1	c.1897A>G	p.Ile633Val	missense_variant	15/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2326A>G	p.Ile776Val	missense_variant	15/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2326A>G	p.Ile776Val	missense_variant	15/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1897A>G	p.Ile633Val	missense_variant	16/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1897A>G	p.Ile633Val	missense_variant	15/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26841 AN: 151972 Hom.: 3899 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0701

Gnomad FIN AF: 0.0531

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0857

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.116 AC: 29026 AN: 251110 Hom.: 2726 AF XY: 0.105 AC XY: 14215 AN XY: 135706

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.0670

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0835

Gnomad OTH exome AF: 0.0908

GnomAD4 exome AF: 0.0955 AC: 139653 AN: 1461840 Hom.: 8875 Cov.: 32 AF XY: 0.0929 AC XY: 67592 AN XY: 727224

Gnomad4 AFR exome AF: 0.410

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0928

Gnomad4 SAS exome AF: 0.0660

Gnomad4 FIN exome AF: 0.0598

Gnomad4 NFE exome AF: 0.0864

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.177 AC: 26926 AN: 152090 Hom.: 3924 Cov.: 32 AF XY: 0.175 AC XY: 13018 AN XY: 74358

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.0971

Gnomad4 EAS AF: 0.0959

Gnomad4 SAS AF: 0.0701

Gnomad4 FIN AF: 0.0531

Gnomad4 NFE AF: 0.0857

Gnomad4 OTH AF: 0.139

Alfa AF: 0.100 Hom.: 2883

Bravo AF: 0.196

TwinsUK AF: 0.0874 AC: 324

ALSPAC AF: 0.0861 AC: 332

ESP6500AA AF: 0.401 AC: 1767

ESP6500EA AF: 0.0837 AC: 720

ExAC AF: 0.119 AC: 14439

Asia WGS AF: 0.124 AC: 432 AN: 3478

EpiCase AF: 0.0814

EpiControl AF: 0.0739

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2007	- -
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	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Arrhythmogenic right ventricular dysplasia 11 Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27153395, 19863551, 25445213) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2015

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.19
DANN	Benign	0.59
DEOGEN2	Benign	0.045	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.042	T;T;T
MetaRNN	Benign	0.00035	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.18	N;N;.
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.019
MPC		0.063
ClinPred		0.00087	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.17

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: rs1893963; hg19: chr18-28649042; COSMIC: COSV51863352;