NM_001943.5:c.3243C>T

Variant names:

• chr18-31546629-C-T
• rs11542379
• NM_001943.5:c.3243C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001943.5(DSG2):​c.3243C>T​(p.Val1081Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,614,172 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (37 hom.)
• Consequence: DSG2 NM_001943.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.0290
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 18-31546629-C-T is Benign according to our data. Variant chr18-31546629-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.029 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1585/152286) while in subpopulation AFR AF = 0.0234 (973/41562). AF 95% confidence interval is 0.0222. There are 16 homozygotes in GnomAd4. There are 746 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

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.3243C>T	p.Val1081Val	synonymous	Exon 15 of 15	NP_001934.2
	DSG2-AS1	NR_045216.1		n.1346-723G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.3243C>T	p.Val1081Val	synonymous	Exon 15 of 15	ENSP00000261590.8
	DSG2	ENST00000713817.1		c.3234C>T	p.Val1078Val	synonymous	Exon 16 of 16	ENSP00000519121.1
	DSG2	ENST00000713819.1		c.3234C>T	p.Val1078Val	synonymous	Exon 17 of 17	ENSP00000519123.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1584 AN: 152168 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00598 AC: 1491 AN: 249366 AF XY: 0.00551

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.00976

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00518

Gnomad OTH exome AF: 0.00975

GnomAD4 exome AF: 0.00481 AC: 7030 AN: 1461886 Hom.: 37 Cov.: 32 AF XY: 0.00461 AC XY: 3354 AN XY: 727244

African (AFR) AF: 0.0232 AC: 777 AN: 33480

American (AMR) AF: 0.00991 AC: 443 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 275 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5768

European-Non Finnish (NFE) AF: 0.00444 AC: 4940 AN: 1112004

Other (OTH) AF: 0.00743 AC: 449 AN: 60396

GnomAD4 genome AF: 0.0104 AC: 1585 AN: 152286 Hom.: 16 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74470

African (AFR) AF: 0.0234 AC: 973 AN: 41562

American (AMR) AF: 0.00961 AC: 147 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00506 AC: 344 AN: 68016

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00900 Hom.: 8

Bravo AF: 0.0117

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00587

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	2	Arrhythmogenic right ventricular dysplasia 10 (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.1
DANN	Benign	0.64
PhyloP100		0.029
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs11542379; hg19: chr18-29126592;