18-31093653-GA-GAA

Variant names:

• chr18-31093653-G-GA
• rs572309510
• NM_024422.6:c.70-11dupT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: DSC2 NM_024422.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.596
• Publications: 0 publications found

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]

DSC2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 18-31093653-G-GA is Benign according to our data. Variant chr18-31093653-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 918626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000673 (10/148670) while in subpopulation AFR AF = 0.000223 (9/40418). AF 95% confidence interval is 0.000115. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.70-11dupT		intron	N/A	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.70-11dupT		intron	N/A	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.-360-11dupT		intron	N/A	NP_001393435.1	A0A3B3ISU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.70-11_70-10insT		intron	N/A	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.70-11_70-10insT		intron	N/A	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.70-11_70-10insT		intron	N/A	ENSP00000519010.1	A0AAQ5BGP6

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

GnomAD2 exomes AF: 0.0000420 AC: 10 AN: 238322 AF XY: 0.0000618

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.0000617

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome 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

African (AFR) AF: 0.000381 AC: 12 AN: 31486

American (AMR) AF: 0.0000475 AC: 2 AN: 42076

Ashkenazi Jewish (ASJ) AF: 0.0000422 AC: 1 AN: 23700

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36932

South Asian (SAS) AF: 0.0000385 AC: 3 AN: 77822

European-Finnish (FIN) AF: 0.0000633 AC: 3 AN: 47412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.0000525 AC: 56 AN: 1066886

Other (OTH) AF: 0.0000355 AC: 2 AN: 56272

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

African (AFR) AF: 0.000223 AC: 9 AN: 40418

American (AMR) AF: 0.00 AC: 0 AN: 14992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67184

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.0000434 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 11 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Familial isolated arrhythmogenic right ventricular dysplasia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.60

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

Other links and lift over

dbSNP: rs572309510; hg19: chr18-28673616; COSMIC: COSV51868800;