18-31521267-T-G

Variant names:

• chr18-31521267-T-G
• rs55657337
• NM_001943.5:c.523+24T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000261590.13(DSG2):​c.523+24T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,383,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DSG2 ENST00000261590.13 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261590.13. 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.523+24T>G		intron	N/A	NP_001934.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.523+24T>G		intron	N/A	ENSP00000261590.8
	DSG2	ENST00000684461.1		n.378T>G		non_coding_transcript_exon	Exon 3 of 3
	DSG2	ENST00000713817.1		c.514+24T>G		intron	N/A	ENSP00000519121.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383542 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 689724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30092

American (AMR) AF: 0.00 AC: 0 AN: 41530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 37420

South Asian (SAS) AF: 0.00 AC: 0 AN: 80264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1055082

Other (OTH) AF: 0.0000174 AC: 1 AN: 57354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00181427), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.16
DANN	Benign	0.30
PhyloP100		-1.0

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: rs55657337; hg19: chr18-29101230;