rs1126214

Variant names:

• chr18-31059582-T-C
• rs1126214
• NM_024422.6:c.*8433A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024422.6(DSC2):​c.*8433A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 152,054 control chromosomes in the GnomAD database, including 9,427 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9427 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: DSC2 NM_024422.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• Publications: 5 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):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.*8433A>G		3_prime_UTR_variant	Exon 16 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.*8641A>G		3_prime_UTR_variant	Exon 17 of 17		NP_004940.1
DSC2	NM_001406506.1	c.*8433A>G		3_prime_UTR_variant	Exon 16 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.*8641A>G		3_prime_UTR_variant	Exon 17 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.*8433A>G		3_prime_UTR_variant	Exon 16 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.*8641A>G		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000251081.6
DSC2	ENST00000713685.1	c.*8433A>G		3_prime_UTR_variant	Exon 16 of 16			ENSP00000518988.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52191 AN: 151936 Hom.: 9417 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.354

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.344 AC: 52239 AN: 152054 Hom.: 9427 Cov.: 32 AF XY: 0.341 AC XY: 25350 AN XY: 74318

African (AFR) AF: 0.289 AC: 11988 AN: 41488

American (AMR) AF: 0.393 AC: 5995 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3468

East Asian (EAS) AF: 0.686 AC: 3535 AN: 5150

South Asian (SAS) AF: 0.345 AC: 1664 AN: 4824

European-Finnish (FIN) AF: 0.263 AC: 2787 AN: 10578

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23811 AN: 67964

Other (OTH) AF: 0.359 AC: 758 AN: 2112

Alfa AF: 0.358 Hom.: 42020

Bravo AF: 0.356

Asia WGS AF: 0.520 AC: 1795 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.67
PhyloP100		0.13

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: rs1126214; hg19: chr18-28639548;