18-31093653-GA-GAA

Variant names:

• chr18-31093653-G-GA
• rs572309510
• NM_024422.6:c.70-11dupT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_024422.6(DSC2):​c.70-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000586 in 1,536,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: DSC2 NM_024422.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.596

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-31093653-G-GA is Benign according to our data. Variant chr18-31093653-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 918626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000673 (10/148670) while in subpopulation AFR AF= 0.000223 (9/40418). AF 95% confidence interval is 0.000115. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.70-11dupT		intron_variant	Intron 1 of 15	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.70-11dupT		intron_variant	Intron 1 of 16		NP_004940.1
DSC2	NM_001406506.1	c.-360-11dupT		intron_variant	Intron 1 of 15		NP_001393435.1
DSC2	NM_001406507.1	c.-360-11dupT		intron_variant	Intron 1 of 16		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.70-11_70-10insT		intron_variant	Intron 1 of 15	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.70-11_70-10insT		intron_variant	Intron 1 of 16	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.-397-11_-397-10insT		intron_variant	Intron 1 of 16			ENSP00000497441.1
DSC2	ENST00000682357.1	c.-360-11_-360-10insT		intron_variant	Intron 1 of 15			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.0000673 AC: 10 AN: 148670 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000576 AC: 80 AN: 1387996 Hom.: 0 Cov.: 25 AF XY: 0.0000565 AC XY: 39 AN XY: 690496

Gnomad4 AFR exome AF: 0.000381

Gnomad4 AMR exome AF: 0.0000475

Gnomad4 ASJ exome AF: 0.0000422

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.0000385

Gnomad4 FIN exome AF: 0.0000633

Gnomad4 NFE exome AF: 0.0000525

Gnomad4 OTH exome AF: 0.0000355

GnomAD4 genome AF: 0.0000673 AC: 10 AN: 148670 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 8 AN XY: 72370

Gnomad4 AFR AF: 0.000223

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DSC2 c.70-11dupT alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.9e-05 in 1536666 control chromosomes, predominantly at a frequency of 0.00029 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.78 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016). To our knowledge, no occurrence of c.70-11dupT in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 918626). Based on the evidence outlined above, the variant was classified as benign. -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 14, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial isolated arrhythmogenic right ventricular dysplasia Benign:1

Sep 17, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs572309510; hg19: chr18-28673616;