NM_024422.6:c.2251-49T>C

Variant names:

• chr18-31069200-A-G
• rs1893962
• NM_024422.6:c.2251-49T>C

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.2251-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,611,092 control chromosomes in the GnomAD database, including 3,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (284 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2876 hom.)
• Consequence: DSC2 NM_024422.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0300
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-31069200-A-G is Benign according to our data. Variant chr18-31069200-A-G is described in ClinVar as Benign. ClinVar VariationId is 261707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0894 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.2251-49T>C		intron	N/A	NP_077740.1
	DSC2	NM_004949.5		c.2251-49T>C		intron	N/A	NP_004940.1
	DSC2	NM_001406506.1		c.1822-49T>C		intron	N/A	NP_001393435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.2251-49T>C		intron	N/A	ENSP00000280904.6
	DSC2	ENST00000251081.8	TSL:1	c.2251-49T>C		intron	N/A	ENSP00000251081.6
	DSC2	ENST00000713707.1		c.2272-49T>C		intron	N/A	ENSP00000519010.1

Frequencies

GnomAD3 genomes AF: 0.0532 AC: 8099 AN: 152156 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.0380

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0668 AC: 16334 AN: 244476 AF XY: 0.0622

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0994

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0544

Gnomad OTH exome AF: 0.0523

GnomAD4 exome AF: 0.0589 AC: 85875 AN: 1458818 Hom.: 2876 Cov.: 31 AF XY: 0.0575 AC XY: 41752 AN XY: 725790

African (AFR) AF: 0.0355 AC: 1185 AN: 33422

American (AMR) AF: 0.145 AC: 6441 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1753 AN: 26112

East Asian (EAS) AF: 0.0926 AC: 3673 AN: 39650

South Asian (SAS) AF: 0.0397 AC: 3417 AN: 86032

European-Finnish (FIN) AF: 0.0349 AC: 1831 AN: 52456

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5764

European-Non Finnish (NFE) AF: 0.0577 AC: 64055 AN: 1110532

Other (OTH) AF: 0.0556 AC: 3355 AN: 60304

GnomAD4 genome AF: 0.0534 AC: 8135 AN: 152274 Hom.: 284 Cov.: 32 AF XY: 0.0540 AC XY: 4023 AN XY: 74454

African (AFR) AF: 0.0385 AC: 1599 AN: 41560

American (AMR) AF: 0.0934 AC: 1429 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3470

East Asian (EAS) AF: 0.0948 AC: 490 AN: 5170

South Asian (SAS) AF: 0.0446 AC: 215 AN: 4824

European-Finnish (FIN) AF: 0.0323 AC: 343 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0547 AC: 3718 AN: 68020

Other (OTH) AF: 0.0477 AC: 101 AN: 2116

Alfa AF: 0.0546 Hom.: 131

Bravo AF: 0.0580

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.46
PhyloP100		-0.030
Mutation Taster		=100/0	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: rs1893962; hg19: chr18-28649166;