rs200691513

Variant names:

• chr18-31545954-A-C
• rs200691513
• NM_001943.5:c.2568A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001943.5(DSG2):​c.2568A>C​(p.Lys856Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.775
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040987134).
• BP6: Variant 18-31545954-A-C is Benign according to our data. Variant chr18-31545954-A-C is described in ClinVar as Benign. ClinVar VariationId is 192185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2568A>C	p.Lys856Asn	missense	Exon 15 of 15	NP_001934.2
	DSG2-AS1	NR_045216.1		n.1346-48T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2568A>C	p.Lys856Asn	missense	Exon 15 of 15	ENSP00000261590.8
	DSG2	ENST00000713817.1		c.2559A>C	p.Lys853Asn	missense	Exon 16 of 16	ENSP00000519121.1
	DSG2	ENST00000713819.1		c.2559A>C	p.Lys853Asn	missense	Exon 17 of 17	ENSP00000519123.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0230 AC: 5496 AN: 239250 AF XY: 0.0177

Gnomad AFR exome AF: 0.0563

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.00753

Gnomad EAS exome AF: 0.0237

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0200

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00279 AC: 4071 AN: 1457766 Hom.: 0 Cov.: 32 AF XY: 0.00289 AC XY: 2097 AN XY: 725122

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00517 AC: 172 AN: 33290

American (AMR) AF: 0.0269 AC: 1181 AN: 43838

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 44 AN: 26082

East Asian (EAS) AF: 0.0141 AC: 554 AN: 39392

South Asian (SAS) AF: 0.000685 AC: 59 AN: 86168

European-Finnish (FIN) AF: 0.0188 AC: 981 AN: 52304

Middle Eastern (MID) AF: 0.000871 AC: 5 AN: 5740

European-Non Finnish (NFE) AF: 0.000832 AC: 924 AN: 1110660

Other (OTH) AF: 0.00250 AC: 151 AN: 60292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000921 AC: 14 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74342

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67838

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0327 AC: 3951

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Cardiomyopathy Benign:1

Aug 18, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.78
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.093
Sift	Benign	0.38	T
Sift4G	Benign	0.37	T
Polyphen		0.87	P
Vest4		0.059
MutPred		0.26		Loss of methylation at K856 (P = 6e-04)
MPC		0.40
ClinPred		0.0092	T
GERP RS		0.67
Varity_R		0.025
gMVP		0.19
Mutation Taster		=91/9	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: rs200691513; hg19: chr18-29125917; COSMIC: COSV55196815; COSMIC: COSV55196815;