rs143040393

chr18-31074782-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_024422.6(DSC2):c.1789G>T(p.Val597Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.654

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03174147).
• BP6: Variant 18-31074782-C-A is Benign according to our data. Variant chr18-31074782-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 199784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31074782-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000585 (89/152226) while in subpopulation AFR AF= 0.00202 (84/41544). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 35 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.1789G>T	p.Val597Phe	missense_variant	12/16	ENST00000280904.11
DSC2	NM_004949.5	c.1789G>T	p.Val597Phe	missense_variant	12/17
DSC2	NM_001406506.1	c.1360G>T	p.Val454Phe	missense_variant	12/16
DSC2	NM_001406507.1	c.1360G>T	p.Val454Phe	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.1789G>T	p.Val597Phe	missense_variant	12/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.1789G>T	p.Val597Phe	missense_variant	12/17	1
DSC2	ENST00000648081.1	c.1360G>T	p.Val454Phe	missense_variant	13/17
DSC2	ENST00000682357.1	c.1360G>T	p.Val454Phe	missense_variant	12/16

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000155 AC: 39 AN: 251108 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135720

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 727188

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74406

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.000327

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: 0.000133 Hom.: 0

Bravo AF: 0.000695

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 19, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 07, 2019

- -

DSC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 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	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	3.2
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.0020	B;B;.
Vest4		0.20
MVP		0.71
MPC		0.098
ClinPred		0.027	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.65

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: rs143040393; hg19: chr18-28654748;