chr18-31093653-G-GA

Position:

• chr18-31093653-G-GA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_024422.6(DSC2):​c.70-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000586 in 1,536,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: DSC2 NM_024422.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.596

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-31093653-G-GA is Benign according to our data. Variant chr18-31093653-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 918626.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.70-11dupT		intron_variant		ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.70-11dupT		intron_variant			NP_004940.1
DSC2	NM_001406506.1	c.-360-11dupT		intron_variant			NP_001393435.1
DSC2	NM_001406507.1	c.-360-11dupT		intron_variant			NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.70-11dupT		intron_variant		1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.70-11dupT		intron_variant		1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.-397-11dupT		intron_variant				ENSP00000497441.1
DSC2	ENST00000682357.1	c.-360-11dupT		intron_variant				ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.0000673 AC: 10 AN: 148670 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

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

GnomAD4 exome AF: 0.0000576 AC: 80 AN: 1387996 Hom.: 0 Cov.: 25 AF XY: 0.0000565 AC XY: 39 AN XY: 690496

Gnomad4 AFR exome AF: 0.000381

Gnomad4 AMR exome AF: 0.0000475

Gnomad4 ASJ exome AF: 0.0000422

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.0000385

Gnomad4 FIN exome AF: 0.0000633

Gnomad4 NFE exome AF: 0.0000525

Gnomad4 OTH exome AF: 0.0000355

GnomAD4 genome AF: 0.0000673 AC: 10 AN: 148670 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 8 AN XY: 72370

Gnomad4 AFR AF: 0.000223

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 06, 2022

- -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 14, 2018

- -

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 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs572309510; hg19: chr18-28673616;