NM_024422.6:c.-113C>T

Variant names:

• chr18-31102084-G-A
• rs866593085
• NM_024422.6:c.-113C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024422.6(DSC2):​c.-113C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000133 in 753,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: DSC2 NM_024422.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.550
• Publications: 0 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]

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.-113C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_024422.6	c.-113C>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000280904.11	NP_077740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.-113C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000280904.11	c.-113C>T		5_prime_UTR_variant	Exon 1 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000133 AC: 1 AN: 753100 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 373708

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14678

American (AMR) AF: 0.00 AC: 0 AN: 9056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13464

East Asian (EAS) AF: 0.00 AC: 0 AN: 25268

South Asian (SAS) AF: 0.00 AC: 0 AN: 38404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2506

European-Non Finnish (NFE) AF: 0.00000170 AC: 1 AN: 587616

Other (OTH) AF: 0.00 AC: 0 AN: 34452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.9
DANN	Benign	0.92
PhyloP100		0.55
PromoterAI		-0.045	Neutral

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: rs866593085; hg19: chr18-28682047;