rs371146201

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001943.5(DSG2):​c.2305G>A​(p.Glu769Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000407 in 1,399,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

2
3
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:1

Conservation

PhyloP100: 3.81
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.23726985).
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DSG2NM_001943.5 linkuse as main transcriptc.2305G>A p.Glu769Lys missense_variant 14/15 ENST00000261590.13
DSG2-AS1NR_045216.1 linkuse as main transcriptn.1810+279C>T intron_variant, non_coding_transcript_variant
DSG2XM_047437315.1 linkuse as main transcriptc.1771G>A p.Glu591Lys missense_variant 15/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DSG2ENST00000261590.13 linkuse as main transcriptc.2305G>A p.Glu769Lys missense_variant 14/151 NM_001943.5 P1
DSG2-AS1ENST00000583706.5 linkuse as main transcriptn.1848+279C>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000129
AC:
18
AN:
139630
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000425
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000805
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000151
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000466
AC:
10
AN:
214594
Hom.:
0
AF XY:
0.0000343
AC XY:
4
AN XY:
116776
show subpopulations
Gnomad AFR exome
AF:
0.000334
Gnomad AMR exome
AF:
0.000117
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000196
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000310
AC:
39
AN:
1260008
Hom.:
0
Cov.:
33
AF XY:
0.0000242
AC XY:
15
AN XY:
620430
show subpopulations
Gnomad4 AFR exome
AF:
0.000714
Gnomad4 AMR exome
AF:
0.000195
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000128
Gnomad4 FIN exome
AF:
0.0000253
Gnomad4 NFE exome
AF:
0.00000202
Gnomad4 OTH exome
AF:
0.000209
GnomAD4 genome
AF:
0.000129
AC:
18
AN:
139630
Hom.:
0
Cov.:
31
AF XY:
0.000135
AC XY:
9
AN XY:
66732
show subpopulations
Gnomad4 AFR
AF:
0.000425
Gnomad4 AMR
AF:
0.0000805
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000151
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000153
Hom.:
0
ESP6500AA
AF:
0.000751
AC:
3
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.0000496
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2
Likely pathogenic, flagged submissionresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research Center-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 12, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 29, 2022- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 13, 2013The Glu769Lys variant in DSG2 has not been reported in individuals with cardiomy opathy but has been identified in 3/3994 African American chromosomes by the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs37114620 1). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an imp act to the protein. Additional information is needed to fully assess the clinica l significance of the Glu769Lys variant. -
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 11, 2024This missense variant replaces glutamic acid with lysine at codon 769 of the DSG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/245478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 27, 2023This missense variant replaces glutamic acid with lysine at codon 769 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 13/245478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Arrhythmogenic right ventricular dysplasia 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 19, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 769 of the DSG2 protein (p.Glu769Lys). This variant is present in population databases (rs371146201, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 163217). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 19, 2021- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.25
T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.24
T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.7
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.23
Sift
Benign
0.20
T
Sift4G
Benign
0.16
T
Polyphen
1.0
D
Vest4
0.25
MVP
0.84
MPC
0.43
ClinPred
0.53
D
GERP RS
6.0
Varity_R
0.092
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371146201; hg19: chr18-29122786; COSMIC: COSV55196604; API