rs139399951

Variant names:

• chr18-31082930-G-A
• rs139399951
• NM_024422.6:c.1073C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-31082930-G-A
• chr18-31082930-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024422.6(DSC2):​c.1073C>T​(p.Thr358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,162 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T358P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.752
• Publications: 10 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=0.009298474).
• BP6: Variant 18-31082930-G-A is Benign according to our data. Variant chr18-31082930-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000985 (150/152326) while in subpopulation AMR AF = 0.00209 (32/15298). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD,SD gene

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.1073C>T	p.Thr358Ile	missense	Exon 8 of 16	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.1073C>T	p.Thr358Ile	missense	Exon 8 of 17	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.644C>T	p.Thr215Ile	missense	Exon 8 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.1073C>T	p.Thr358Ile	missense	Exon 8 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.1073C>T	p.Thr358Ile	missense	Exon 8 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.1073C>T	p.Thr358Ile	missense	Exon 8 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00133 AC: 335 AN: 250956 AF XY: 0.00131

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00119 AC: 1738 AN: 1460836 Hom.: 4 Cov.: 31 AF XY: 0.00119 AC XY: 862 AN XY: 726772

African (AFR) AF: 0.000120 AC: 4 AN: 33450

American (AMR) AF: 0.00116 AC: 52 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00412 AC: 220 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00126 AC: 1404 AN: 1111742

Other (OTH) AF: 0.000962 AC: 58 AN: 60318

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00115 AC XY: 86 AN XY: 74490

African (AFR) AF: 0.000217 AC: 9 AN: 41564

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.000895

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Arrhythmogenic right ventricular dysplasia 11 (5)
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiac arrest (1)
-	-	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	0.15
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-0.75
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.057
Sift	Benign	0.056	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.54
MPC		0.080
ClinPred		0.048	T
GERP RS		1.4
Varity_R		0.097
gMVP		0.46
Mutation Taster		=94/6	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: rs139399951; hg19: chr18-28662896;