18-31498158-G-C

Variant names:

• chr18-31498158-G-C
• rs149048465
• ENST00000713817.1:c.-278G>C

Variant summary

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

The ENST00000713817.1(DSG2):​c.-278G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,152,284 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (63 hom.)
• Consequence: DSG2 ENST00000713817.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.173
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-31498158-G-C is Benign according to our data. Variant chr18-31498158-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 326465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000713817.1. 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.-94G>C		upstream_gene	N/A	NP_001934.2	Q14126

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000713817.1		c.-278G>C		5_prime_UTR	Exon 1 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.-316G>C		5_prime_UTR	Exon 1 of 17	ENSP00000519123.1	A0AAQ5BGZ7
	DSG2	ENST00000713822.1		c.-347G>C		5_prime_UTR	Exon 1 of 17	ENSP00000519126.1	A0AAQ5BGX5

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 700 AN: 151836 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0533

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00691

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00814

GnomAD4 exome AF: 0.00356 AC: 3565 AN: 1000340 Hom.: 63 Cov.: 16 AF XY: 0.00364 AC XY: 1726 AN XY: 474024

African (AFR) AF: 0.000433 AC: 9 AN: 20776

American (AMR) AF: 0.00574 AC: 42 AN: 7316

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 52 AN: 12464

East Asian (EAS) AF: 0.0666 AC: 1552 AN: 23308

South Asian (SAS) AF: 0.00120 AC: 22 AN: 18304

European-Finnish (FIN) AF: 0.00911 AC: 195 AN: 21414

Middle Eastern (MID) AF: 0.0156 AC: 42 AN: 2694

European-Non Finnish (NFE) AF: 0.00170 AC: 1456 AN: 854432

Other (OTH) AF: 0.00492 AC: 195 AN: 39632

GnomAD4 genome AF: 0.00459 AC: 698 AN: 151944 Hom.: 11 Cov.: 32 AF XY: 0.00517 AC XY: 384 AN XY: 74288

African (AFR) AF: 0.000458 AC: 19 AN: 41484

American (AMR) AF: 0.00530 AC: 81 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.0533 AC: 273 AN: 5124

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.00691 AC: 73 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00309 AC: 210 AN: 67894

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00468

Asia WGS AF: 0.0250 AC: 87 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Benign	0.47
PhyloP100		-0.17
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.2
Mutation Taster		=300/0	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: rs149048465; hg19: chr18-29078121;