rs1042769

Variant names:

• chr18-31545891-A-G
• rs1042769
• NM_001943.5:c.2505A>G
• DSG2 p.Thr835Thr

Your query was ambiguous. Multiple possible variants found:

• chr18-31545891-A-G
• chr18-31545891-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001943.5(DSG2):​c.2505A>G​(p.Thr835Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,976 control chromosomes in the GnomAD database, including 13,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T835T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3247 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10258 hom.)
• Consequence: DSG2 NM_001943.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -2.77
• Publications: 20 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-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 18-31545891-A-G is Benign according to our data. Variant chr18-31545891-A-G is described in ClinVar as Benign. ClinVar VariationId is 44302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

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.2505A>G	p.Thr835Thr	synonymous	Exon 15 of 15	NP_001934.2	Q14126
	DSG2-AS1	NR_045216.1		n.1361T>C		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2505A>G	p.Thr835Thr	synonymous	Exon 15 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.2496A>G	p.Thr832Thr	synonymous	Exon 16 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.2496A>G	p.Thr832Thr	synonymous	Exon 17 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26974 AN: 151986 Hom.: 3236 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.125 AC: 31107 AN: 249234 AF XY: 0.120

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.0722

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.110 AC: 160751 AN: 1461874 Hom.: 10258 Cov.: 32 AF XY: 0.108 AC XY: 78724 AN XY: 727242

African (AFR) AF: 0.351 AC: 11759 AN: 33480

American (AMR) AF: 0.129 AC: 5777 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3505 AN: 26136

East Asian (EAS) AF: 0.201 AC: 7972 AN: 39700

South Asian (SAS) AF: 0.0753 AC: 6492 AN: 86258

European-Finnish (FIN) AF: 0.0707 AC: 3775 AN: 53414

Middle Eastern (MID) AF: 0.153 AC: 880 AN: 5768

European-Non Finnish (NFE) AF: 0.102 AC: 113080 AN: 1112002

Other (OTH) AF: 0.124 AC: 7511 AN: 60392

GnomAD4 genome AF: 0.178 AC: 27023 AN: 152102 Hom.: 3247 Cov.: 32 AF XY: 0.174 AC XY: 12923 AN XY: 74358

African (AFR) AF: 0.344 AC: 14263 AN: 41444

American (AMR) AF: 0.153 AC: 2332 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.208 AC: 1077 AN: 5170

South Asian (SAS) AF: 0.0906 AC: 437 AN: 4824

European-Finnish (FIN) AF: 0.0598 AC: 635 AN: 10612

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7285 AN: 67990

Other (OTH) AF: 0.164 AC: 345 AN: 2110

Alfa AF: 0.137 Hom.: 3225

Bravo AF: 0.191

Asia WGS AF: 0.185 AC: 644 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Arrhythmogenic right ventricular dysplasia 10 (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.17
DANN	Benign	0.71
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1042769;

hg19: chr18-29125854;

COSMIC: COSV55200374;

COSMIC: COSV55200374;