rs79068489

chr18-31546681-A-Gchr18-31546681-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001943.5(DSG2):c.3295A>G(p.Thr1099Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1099I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.0470

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002890557).
• BP6: Variant 18-31546681-A-G is Benign according to our data. Variant chr18-31546681-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44314.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=1, Benign=3}. Variant chr18-31546681-A-G is described in Lovd as [Benign]. Variant chr18-31546681-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00128 (195/152268) while in subpopulation AFR AF= 0.00448 (186/41550). AF 95% confidence interval is 0.00395. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.3295A>G	p.Thr1099Ala	missense_variant	15/15	ENST00000261590.13
DSG2-AS1	NR_045216.1	n.1346-775T>C		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1	c.2761A>G	p.Thr921Ala	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.3295A>G	p.Thr1099Ala	missense_variant	15/15	1	NM_001943.5	P1
DSG2-AS1	ENST00000583706.5	n.1384-775T>C		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1	n.697-775T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 74 AN: 249180 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135178

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0000579

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: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461878 Hom.: 1 Cov.: 32 AF XY: 0.000149 AC XY: 108 AN XY: 727232

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74458

Gnomad4 AFR AF: 0.00448

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.00125

ESP6500AA AF: 0.00399 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000405 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	DSG2 NM_001943.4 exon 15 p.Thr1099Ala (c.3295A>G): This variant has not been reported in the literature and is present in 0.4% (98/24186) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-29126644-A-G). This variant is also present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:44314). This variant amino acid Alanine (Ala) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2012	Thr1099Ala in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (15/3328) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs79068489). Thr1099Ala in exon 15 of DSG2 (r s79068489; allele frequency = 0.5%, 15/3328) ** -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2020	Variant summary: DSG2 c.3295A>G (p.Thr1099Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 281622 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 410 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3295A>G has been reported in the literature in one individual affected with DCM (Garcia-Pavia_2011). The data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 20, 2018	- -

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	This variant is associated with the following publications: (PMID: 21636032, 21859740) -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

DSG2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2018

This 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	0.063
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.8
Dann	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.029
Sift	Benign	0.19	T
Sift4G	Benign	0.11	T
Polyphen		0.012	B
Vest4		0.037
MVP		0.63
MPC		0.072
ClinPred		0.030	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs79068489; hg19: chr18-29126644;