18-31521252-CTTTT-CT

Variant names:

• chr18-31521252-CTTT-C
• rs77324780
• NM_001943.5:c.523+22_523+24delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001943.5(DSG2):​c.523+22_523+24delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,386,746 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DSG2 NM_001943.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.139
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.523+22_523+24delTTT		intron	N/A	NP_001934.2	Q14126

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.523+22_523+24delTTT		intron	N/A	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.514+22_514+24delTTT		intron	N/A	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.514+22_514+24delTTT		intron	N/A	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.00000742 AC: 1 AN: 134748 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.000246 AC: 31 AN: 126002 AF XY: 0.000200

Gnomad AFR exome AF: 0.000643

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000232

Gnomad FIN exome AF: 0.000282

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000133 AC: 166 AN: 1251998 Hom.: 0 AF XY: 0.000128 AC XY: 80 AN XY: 626068

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

African (AFR) AF: 0.000150 AC: 4 AN: 26622

American (AMR) AF: 0.000228 AC: 8 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23090

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35810

South Asian (SAS) AF: 0.0000967 AC: 7 AN: 72410

European-Finnish (FIN) AF: 0.000271 AC: 12 AN: 44338

Middle Eastern (MID) AF: 0.000212 AC: 1 AN: 4716

European-Non Finnish (NFE) AF: 0.000133 AC: 127 AN: 957722

Other (OTH) AF: 0.000115 AC: 6 AN: 52184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000742 AC: 1 AN: 134748 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 65188

African (AFR) AF: 0.0000269 AC: 1 AN: 37220

American (AMR) AF: 0.00 AC: 0 AN: 13126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3178

East Asian (EAS) AF: 0.00 AC: 0 AN: 4634

South Asian (SAS) AF: 0.00 AC: 0 AN: 4144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61720

Other (OTH) AF: 0.00 AC: 0 AN: 1828

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77324780; hg19: chr18-29101215;