rs117812913

Variant names:

• chr18-31092104-T-C
• rs117812913
• NM_024422.6:c.351A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024422.6(DSC2):​c.351A>G​(p.Thr117Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00935 in 1,611,618 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (90 hom.)
• Consequence: DSC2 NM_024422.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.631
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-31092104-T-C is Benign according to our data. Variant chr18-31092104-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.631 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00798 (1215/152332) while in subpopulation NFE AF = 0.0132 (897/68030). AF 95% confidence interval is 0.0125. There are 8 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR,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.351A>G	p.Thr117Thr	synonymous	Exon 3 of 16	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.351A>G	p.Thr117Thr	synonymous	Exon 3 of 17	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.-79A>G		5_prime_UTR	Exon 3 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.351A>G	p.Thr117Thr	synonymous	Exon 3 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.351A>G	p.Thr117Thr	synonymous	Exon 3 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.351A>G	p.Thr117Thr	synonymous	Exon 3 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1215 AN: 152214 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00837 AC: 2098 AN: 250692 AF XY: 0.00820

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.00949 AC: 13847 AN: 1459286 Hom.: 90 Cov.: 31 AF XY: 0.00919 AC XY: 6674 AN XY: 725994

African (AFR) AF: 0.00129 AC: 43 AN: 33408

American (AMR) AF: 0.00284 AC: 127 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86102

European-Finnish (FIN) AF: 0.0197 AC: 1051 AN: 53366

Middle Eastern (MID) AF: 0.00670 AC: 35 AN: 5220

European-Non Finnish (NFE) AF: 0.0107 AC: 11841 AN: 1110570

Other (OTH) AF: 0.00833 AC: 502 AN: 60258

GnomAD4 genome AF: 0.00798 AC: 1215 AN: 152332 Hom.: 8 Cov.: 32 AF XY: 0.00805 AC XY: 600 AN XY: 74494

African (AFR) AF: 0.00135 AC: 56 AN: 41584

American (AMR) AF: 0.00327 AC: 50 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.0175 AC: 186 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 897 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.0113 Hom.: 11

Bravo AF: 0.00614

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00972

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)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.68
PhyloP100		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117812913; hg19: chr18-28672067;