18-31521252-CTTTT-CTT

Position:

• chr18-31521252-CTTTT-CTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001943.5(DSG2):​c.523+23_523+24delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0073 in 1,349,226 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (3 hom.)
• Consequence: DSG2 NM_001943.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.123

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 18-31521252-CTT-C is Benign according to our data. Variant chr18-31521252-CTT-C is described in ClinVar as [Benign]. Clinvar id is 466344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31521252-CTT-C is described in Lovd as [Benign]. Variant chr18-31521252-CTT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00387 (521/134684) while in subpopulation NFE AF= 0.00635 (392/61700). AF 95% confidence interval is 0.00583. There are 3 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.523+23_523+24delTT		intron_variant		ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-12+23_-12+24delTT		intron_variant			XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.523+23_523+24delTT		intron_variant		1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 521 AN: 134686 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000752

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00175

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000216

Gnomad SAS AF: 0.000724

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00274

GnomAD4 exome AF: 0.00768 AC: 9330 AN: 1214542 Hom.: 3 AF XY: 0.00744 AC XY: 4523 AN XY: 607834

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.00684

Gnomad4 ASJ exome AF: 0.00271

Gnomad4 EAS exome AF: 0.00223

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.00832

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00387 AC: 521 AN: 134684 Hom.: 3 Cov.: 32 AF XY: 0.00402 AC XY: 262 AN XY: 65176

Gnomad4 AFR AF: 0.000751

Gnomad4 AMR AF: 0.00175

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000216

Gnomad4 SAS AF: 0.000728

Gnomad4 FIN AF: 0.00894

Gnomad4 NFE AF: 0.00635

Gnomad4 OTH AF: 0.00272

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 18, 2022

- -

Arrhythmogenic right ventricular dysplasia 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2017

- -

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: rs77324780; hg19: chr18-29101215;