rs765067237
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024422.6(DSC2):āc.2245A>Cā(p.Lys749Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2245A>C | p.Lys749Gln | missense_variant | 14/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.2245A>C | p.Lys749Gln | missense_variant | 14/17 | ||
DSC2 | NM_001406506.1 | c.1816A>C | p.Lys606Gln | missense_variant | 14/16 | ||
DSC2 | NM_001406507.1 | c.1816A>C | p.Lys606Gln | missense_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2245A>C | p.Lys749Gln | missense_variant | 14/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.2245A>C | p.Lys749Gln | missense_variant | 14/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1816A>C | p.Lys606Gln | missense_variant | 15/17 | ||||
DSC2 | ENST00000682357.1 | c.1816A>C | p.Lys606Gln | missense_variant | 14/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000525 AC: 8AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251272Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135800
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461476Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727032
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74384
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 749 of the DSC2 protein (p.Lys749Gln). This variant is present in population databases (rs765067237, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 199771). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 01, 2023 | This missense variant replaces lysine with glutamine at codon 749 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 5/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2019 | The p.K749Q variant (also known as c.2245A>C), located in coding exon 14 of the DSC2 gene, results from an A to C substitution at nucleotide position 2245. The lysine at codon 749 is replaced by glutamine, an amino acid with similar properties. This variant was detected in an exome sequencing cohort and was not reported as a primary or secondary finding; however clinical details were limited (Sapp JC et al. Am. J. Hum. Genet..2018 09;103(3):358-366). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces lysine with glutamine at codon 749 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at