DSG2 p.Ile293Val

Variant names:

• chr18-31524751-A-G
• rs2230234
• NM_001943.5:c.877A>G
• DSG2 p.Ile293Val

Your query was ambiguous. Multiple possible variants found:

• chr18-31524751-A-G
• chr18-31524751-ATA-GTT
• chr18-31524751-ATA-GTC
• chr18-31524751-ATA-GTG

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001943.5(DSG2):​c.877A>G​(p.Ile293Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,614,152 control chromosomes in the GnomAD database, including 5,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I293L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.065 (476 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5096 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 2.20
• Publications: 41 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: G2P, Labcorp Genetics (formerly Invitae), 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026659071).
• BP6: Variant 18-31524751-A-G is Benign according to our data. Variant chr18-31524751-A-G is described in ClinVar as Benign. ClinVar VariationId is 44331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0866 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.877A>G	p.Ile293Val	missense	Exon 8 of 15	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.877A>G	p.Ile293Val	missense	Exon 8 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.868A>G	p.Ile290Val	missense	Exon 9 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.868A>G	p.Ile290Val	missense	Exon 10 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9832 AN: 152196 Hom.: 476 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0790

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.0627

GnomAD2 exomes AF: 0.0687 AC: 17121 AN: 249370 AF XY: 0.0705

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0395

Gnomad ASJ exome AF: 0.0770

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.0865

Gnomad OTH exome AF: 0.0838

GnomAD4 exome AF: 0.0794 AC: 116110 AN: 1461838 Hom.: 5096 Cov.: 37 AF XY: 0.0791 AC XY: 57542 AN XY: 727222

African (AFR) AF: 0.0134 AC: 447 AN: 33480

American (AMR) AF: 0.0418 AC: 1870 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 2033 AN: 26134

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39688

South Asian (SAS) AF: 0.0452 AC: 3903 AN: 86256

European-Finnish (FIN) AF: 0.141 AC: 7553 AN: 53420

Middle Eastern (MID) AF: 0.0912 AC: 526 AN: 5766

European-Non Finnish (NFE) AF: 0.0857 AC: 95289 AN: 1111978

Other (OTH) AF: 0.0742 AC: 4479 AN: 60394

GnomAD4 genome AF: 0.0645 AC: 9831 AN: 152314 Hom.: 476 Cov.: 33 AF XY: 0.0665 AC XY: 4954 AN XY: 74486

African (AFR) AF: 0.0153 AC: 636 AN: 41574

American (AMR) AF: 0.0489 AC: 748 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0790 AC: 274 AN: 3470

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.0417 AC: 201 AN: 4824

European-Finnish (FIN) AF: 0.152 AC: 1609 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0885 AC: 6017 AN: 68020

Other (OTH) AF: 0.0621 AC: 131 AN: 2110

Alfa AF: 0.0773 Hom.: 1793

Bravo AF: 0.0552

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0848

EpiControl AF: 0.0859

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	not provided (3)
-	-	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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.089
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.053	T
Varity_R		0.29
gMVP		0.38
Mutation Taster		=84/16	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: rs2230234;

hg19: chr18-29104714;

COSMIC: COSV107226301;