rs140232809

Positions:

• chr18-31074796-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_024422.6(DSC2):​c.1775C>T​(p.Ala592Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 2.92

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011348993).
• BP6: Variant 18-31074796-G-A is Benign according to our data. Variant chr18-31074796-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163184.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr18-31074796-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000329 (50/152188) while in subpopulation AFR AF= 0.00111 (46/41532). AF 95% confidence interval is 0.000853. There are 0 homozygotes in gnomad4. There are 25 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	Protein	UniProt
DSC2	NM_024422.6	c.1775C>T	p.Ala592Val	missense_variant	12/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1775C>T	p.Ala592Val	missense_variant	12/17		NP_004940.1
DSC2	NM_001406506.1	c.1346C>T	p.Ala449Val	missense_variant	12/16		NP_001393435.1
DSC2	NM_001406507.1	c.1346C>T	p.Ala449Val	missense_variant	12/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1775C>T	p.Ala592Val	missense_variant	12/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1775C>T	p.Ala592Val	missense_variant	12/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1346C>T	p.Ala449Val	missense_variant	13/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1346C>T	p.Ala449Val	missense_variant	12/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000147 AC: 37 AN: 251044 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135668

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727180

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74410

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000262

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

Alfa AF: 0.0000790 Hom.: 0

Bravo AF: 0.000434

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2014	The Ala592Val variant in DSC2 has been reported in 1 adult with DCM (Elliott 201 0). However, it has also been identified in 1 adult healthy control (Kapplinger 2010) and in 0.1% (6/4406) of African American chromosomes screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs140232809) . Computational prediction tools and conservation analysis suggest that this var iant may not impact the protein, though this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of the Ala592 Val variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2014	p.Ala592Val (GCG>GTG): c.1775 C>T in exon 12 of the DSC2 gene (NM_024422.3). The Ala592Val variant in the DSC2 gene has been reported in one patient with dilated cardiomyopathy (DCM) and it was classified as a variant of unknown significance (Elliott P et al., 2010). Ala592Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is not well conserved across species. In silico analysis predicts Ala592Val is benign to the protein structure/function. The NHLBI Exome Sequencing Project and 1,000 Genomes project identified the Ala592Val variant with a frequency of 0.1-0.4% in individuals of African American ancestry. Kapplinger et al. also reported Ala592Val in 1/427 healthy control subjects. However, mutations in a nearby codon (Ile603Thr, Ile603Leu) have been reported in association with ARVC, supporting the functional importance of this region of the protein. With the clinical and molecular information available at this time, we cannot definitively determine if Ala592Val is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s). -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2020	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.054	T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.046
Sift	Benign	0.42	T;T;.
Sift4G	Benign	0.51	T;T;.
Polyphen		0.0030	B;B;.
Vest4		0.12
MVP		0.64
MPC		0.093
ClinPred		0.013	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.48

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: rs140232809; hg19: chr18-28654762; COSMIC: COSV99199797;