rs142807209

chr18-31070750-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_024422.6(DSC2):c.2226A>G(p.Thr742=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DSC2 NM_024422.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.27

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-31070750-T-C is Benign according to our data. Variant chr18-31070750-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 468377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.27 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.2226A>G	p.Thr742=	synonymous_variant	14/16	ENST00000280904.11
DSC2	NM_004949.5	c.2226A>G	p.Thr742=	synonymous_variant	14/17
DSC2	NM_001406506.1	c.1797A>G	p.Thr599=	synonymous_variant	14/16
DSC2	NM_001406507.1	c.1797A>G	p.Thr599=	synonymous_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.2226A>G	p.Thr742=	synonymous_variant	14/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.2226A>G	p.Thr742=	synonymous_variant	14/17	1
DSC2	ENST00000648081.1	c.1797A>G	p.Thr599=	synonymous_variant	15/17
DSC2	ENST00000682357.1	c.1797A>G	p.Thr599=	synonymous_variant	14/16

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251314 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135820

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000289

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: 0.0000116 AC: 17 AN: 1461576 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727088

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000331

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74392

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000204

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 09, 2023

- -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 04, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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. -

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

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.044
Dann	Benign	0.62

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: rs142807209; hg19: chr18-28650716;