NM_001943.5:c.2137G>A

Variant names:

• chr18-31542655-G-A
• rs79241126
• NM_001943.5:c.2137G>A

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.2137G>A​(p.Glu713Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,614,098 control chromosomes in the GnomAD database, including 4,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E713A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (284 hom., cov: 31)
  • Exomes 𝑓: 0.069 (4023 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.591
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019516647).
• BP6: Variant 18-31542655-G-A is Benign according to our data. Variant chr18-31542655-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 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.2137G>A	p.Glu713Lys	missense	Exon 14 of 15	NP_001934.2	Q14126
	DSG2-AS1	NR_045216.1		n.1811-334C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2137G>A	p.Glu713Lys	missense	Exon 14 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.2128G>A	p.Glu710Lys	missense	Exon 15 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.2128G>A	p.Glu710Lys	missense	Exon 16 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8079 AN: 152096 Hom.: 284 Cov.: 31

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0529 AC: 13204 AN: 249434 AF XY: 0.0525

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0578

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.0750

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0689 AC: 100729 AN: 1461884 Hom.: 4023 Cov.: 31 AF XY: 0.0672 AC XY: 48888 AN XY: 727242

African (AFR) AF: 0.00953 AC: 319 AN: 33480

American (AMR) AF: 0.0339 AC: 1518 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0606 AC: 1585 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0134 AC: 1156 AN: 86258

European-Finnish (FIN) AF: 0.0992 AC: 5299 AN: 53418

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.0783 AC: 87021 AN: 1112006

Other (OTH) AF: 0.0624 AC: 3767 AN: 60396

GnomAD4 genome AF: 0.0531 AC: 8078 AN: 152214 Hom.: 284 Cov.: 31 AF XY: 0.0533 AC XY: 3964 AN XY: 74414

African (AFR) AF: 0.0131 AC: 545 AN: 41544

American (AMR) AF: 0.0419 AC: 640 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4826

European-Finnish (FIN) AF: 0.102 AC: 1079 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0784 AC: 5333 AN: 68004

Other (OTH) AF: 0.0540 AC: 114 AN: 2110

Alfa AF: 0.0653 Hom.: 823

Bravo AF: 0.0475

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0708 AC: 273

ESP6500AA AF: 0.0180 AC: 72

ESP6500EA AF: 0.0777 AC: 652

ExAC AF: 0.0518 AC: 6264

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0698

EpiControl AF: 0.0708

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Arrhythmogenic right ventricular cardiomyopathy (2)
-	-	2	Arrhythmogenic right ventricular dysplasia 10 (2)
-	-	2	Cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.59
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.91	P
Vest4		0.096
MPC		0.12
ClinPred		0.0070	T
GERP RS		3.2
Varity_R		0.062
gMVP		0.57
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs79241126; hg19: chr18-29122618; COSMIC: COSV107226276;