NM_001943.5:c.2328C>A

Variant names:

• chr18-31542846-C-A
• rs771104668
• NM_001943.5:c.2328C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001943.5(DSG2):​c.2328C>A​(p.Phe776Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000862 in 1,473,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. F776S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000038 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 1.91
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3659311).

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.2328C>A	p.Phe776Leu	missense	Exon 14 of 15	NP_001934.2	Q14126
	DSG2-AS1	NR_045216.1		n.1810+256G>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.2328C>A	p.Phe776Leu	missense	Exon 14 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.2319C>A	p.Phe773Leu	missense	Exon 15 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.2319C>A	p.Phe773Leu	missense	Exon 16 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.0000376 AC: 5 AN: 133022 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000567 AC: 11 AN: 193924 AF XY: 0.0000575

Gnomad AFR exome AF: 0.0000680

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000966

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000910 AC: 122 AN: 1340536 Hom.: 0 Cov.: 33 AF XY: 0.0000924 AC XY: 61 AN XY: 660334

African (AFR) AF: 0.0000680 AC: 2 AN: 29418

American (AMR) AF: 0.00 AC: 0 AN: 32416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21244

East Asian (EAS) AF: 0.00 AC: 0 AN: 38518

South Asian (SAS) AF: 0.00 AC: 0 AN: 72526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.000116 AC: 120 AN: 1035978

Other (OTH) AF: 0.00 AC: 0 AN: 55098

GnomAD4 genome AF: 0.0000376 AC: 5 AN: 133022 Hom.: 0 Cov.: 26 AF XY: 0.0000478 AC XY: 3 AN XY: 62706

African (AFR) AF: 0.0000595 AC: 2 AN: 33608

American (AMR) AF: 0.00 AC: 0 AN: 11350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 4668

South Asian (SAS) AF: 0.00 AC: 0 AN: 4326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.0000456 AC: 3 AN: 65796

Other (OTH) AF: 0.00 AC: 0 AN: 1784

Alfa AF: 0.000209 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular cardiomyopathy (1)
-	1	-	Arrhythmogenic right ventricular dysplasia 10 (1)
-	1	-	Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB (1)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1BB (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.21
MutPred		0.38		Gain of helix (P = 0.0078)
MVP		0.84
MPC		0.15
ClinPred		0.28	T
GERP RS		3.0
Varity_R		0.64
gMVP		0.53
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs771104668; hg19: chr18-29122809;