18-31069076-T-C

Variant names:

• chr18-31069076-T-C
• rs1893963
• NM_024422.6:c.2326A>G

Variant summary

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

The NM_024422.6(DSC2):​c.2326A>G​(p.Ile776Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,930 control chromosomes in the GnomAD database, including 12,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I776M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3924 hom., cov: 32)
  • Exomes 𝑓: 0.096 (8875 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.0600
• Publications: 34 publications found

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

DSC2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.502965E-4).
• BP6: Variant 18-31069076-T-C is Benign according to our data. Variant chr18-31069076-T-C is described in ClinVar as Benign. ClinVar VariationId is 46178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. 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
	DSC2	NM_024422.6	MANE Select	c.2326A>G	p.Ile776Val	missense	Exon 15 of 16	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.2326A>G	p.Ile776Val	missense	Exon 15 of 17	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.1897A>G	p.Ile633Val	missense	Exon 15 of 16	NP_001393435.1	A0A3B3ISU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.2326A>G	p.Ile776Val	missense	Exon 15 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.2326A>G	p.Ile776Val	missense	Exon 15 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.2347A>G	p.Ile783Val	missense	Exon 15 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26841 AN: 151972 Hom.: 3899 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0701

Gnomad FIN AF: 0.0531

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0857

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.116 AC: 29026 AN: 251110 AF XY: 0.105

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0835

Gnomad OTH exome AF: 0.0908

GnomAD4 exome AF: 0.0955 AC: 139653 AN: 1461840 Hom.: 8875 Cov.: 32 AF XY: 0.0929 AC XY: 67592 AN XY: 727224

African (AFR) AF: 0.410 AC: 13725 AN: 33480

American (AMR) AF: 0.175 AC: 7834 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2663 AN: 26134

East Asian (EAS) AF: 0.0928 AC: 3685 AN: 39694

South Asian (SAS) AF: 0.0660 AC: 5693 AN: 86254

European-Finnish (FIN) AF: 0.0598 AC: 3197 AN: 53420

Middle Eastern (MID) AF: 0.0995 AC: 574 AN: 5768

European-Non Finnish (NFE) AF: 0.0864 AC: 96100 AN: 1111978

Other (OTH) AF: 0.102 AC: 6182 AN: 60392

GnomAD4 genome AF: 0.177 AC: 26926 AN: 152090 Hom.: 3924 Cov.: 32 AF XY: 0.175 AC XY: 13018 AN XY: 74358

African (AFR) AF: 0.400 AC: 16580 AN: 41412

American (AMR) AF: 0.153 AC: 2343 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3470

East Asian (EAS) AF: 0.0959 AC: 496 AN: 5170

South Asian (SAS) AF: 0.0701 AC: 338 AN: 4820

European-Finnish (FIN) AF: 0.0531 AC: 564 AN: 10612

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5829 AN: 68014

Other (OTH) AF: 0.139 AC: 294 AN: 2114

Alfa AF: 0.112 Hom.: 6945

Bravo AF: 0.196

TwinsUK AF: 0.0874 AC: 324

ALSPAC AF: 0.0861 AC: 332

ESP6500AA AF: 0.401 AC: 1767

ESP6500EA AF: 0.0837 AC: 720

ExAC AF: 0.119 AC: 14439

Asia WGS AF: 0.124 AC: 432 AN: 3478

EpiCase AF: 0.0814

EpiControl AF: 0.0739

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Arrhythmogenic right ventricular dysplasia 11 (5)
-	-	2	Cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial isolated arrhythmogenic right ventricular dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.19
DANN	Benign	0.59
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.00035	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.060
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.063
ClinPred		0.00087	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.17
Mutation Taster		=99/1	polymorphism (auto)

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: rs1893963; hg19: chr18-28649042; COSMIC: COSV51863352;