rs1555669691

Variant names:

• chr18-31498293-C-T
• rs1555669691
• NM_001943.5:c.42C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001943.5(DSG2):​c.42C>T​(p.Leu14Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSG2 NM_001943.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.275
• Publications: 0 publications found

Genes affected

DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

DSG2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1BB

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 18-31498293-C-T is Benign according to our data. Variant chr18-31498293-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 466342.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.275 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001943.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.42C>T	p.Leu14Leu	synonymous	Exon 1 of 15	NP_001934.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.42C>T	p.Leu14Leu	synonymous	Exon 1 of 15	ENSP00000261590.8
	DSG2	ENST00000713821.1		c.42C>T	p.Leu14Leu	synonymous	Exon 1 of 14	ENSP00000519125.1
	DSG2	ENST00000713823.1		c.42C>T	p.Leu14Leu	synonymous	Exon 1 of 15	ENSP00000519127.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1112692 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 528862

African (AFR) AF: 0.00 AC: 0 AN: 23512

American (AMR) AF: 0.00 AC: 0 AN: 9758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14546

East Asian (EAS) AF: 0.00 AC: 0 AN: 27390

South Asian (SAS) AF: 0.00 AC: 0 AN: 21096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 931652

Other (OTH) AF: 0.00 AC: 0 AN: 44540

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.3
DANN	Benign	0.93
PhyloP100		0.28
PromoterAI		0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1555669691; hg19: chr18-29078256;