chr18-31070723-T-C
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_024422.6(DSC2):c.2250+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
DSC2
NM_024422.6 splice_donor_region, intron
NM_024422.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.01139
2
Clinical Significance
Conservation
PhyloP100: 0.409
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.3).
BP6
Variant 18-31070723-T-C is Benign according to our data. Variant chr18-31070723-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468378.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2250+3A>G | splice_donor_region_variant, intron_variant | ENST00000280904.11 | |||
DSC2 | NM_001406506.1 | c.1821+3A>G | splice_donor_region_variant, intron_variant | ||||
DSC2 | NM_001406507.1 | c.1821+3A>G | splice_donor_region_variant, intron_variant | ||||
DSC2 | NM_004949.5 | c.2250+3A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2250+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_024422.6 | P1 | |||
DSC2 | ENST00000251081.8 | c.2250+3A>G | splice_donor_region_variant, intron_variant | 1 | |||||
DSC2 | ENST00000648081.1 | c.1821+3A>G | splice_donor_region_variant, intron_variant | ||||||
DSC2 | ENST00000682357.1 | c.1821+3A>G | splice_donor_region_variant, intron_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461414Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727000
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2022 | This sequence change falls in intron 14 of the DSC2 gene. It does not directly change the encoded amino acid sequence of the DSC2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 468378). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
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Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at