rs397517390

Variant names:

• chr18-31082266-GT-G
• rs397517390
• NM_024422.6:c.1234delA

Your query was ambiguous. Multiple possible variants found:

• chr18-31082266-GT-G
• chr18-31082266-GT-GTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024422.6(DSC2):​c.1234delA​(p.Thr412ProfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31082266-GT-G is Pathogenic according to our data. Variant chr18-31082266-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1234delA	p.Thr412ProfsTer8	frameshift_variant	Exon 9 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1234delA	p.Thr412ProfsTer8	frameshift_variant	Exon 9 of 17		NP_004940.1
DSC2	NM_001406506.1	c.805delA	p.Thr269ProfsTer8	frameshift_variant	Exon 9 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.805delA	p.Thr269ProfsTer8	frameshift_variant	Exon 9 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1234delA	p.Thr412ProfsTer8	frameshift_variant	Exon 9 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1234delA	p.Thr412ProfsTer8	frameshift_variant	Exon 9 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.805delA	p.Thr269ProfsTer8	frameshift_variant	Exon 10 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.805delA	p.Thr269ProfsTer8	frameshift_variant	Exon 9 of 16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461252 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726912

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33460

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26116

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39620

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86182

Gnomad4 FIN exome AF: 0.0000188 AC: 1 AN: 53236

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1111806

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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: rs397517390; hg19: chr18-28662232;