rs202108848
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000722.4(CACNA2D1):c.2333C>T(p.Ser778Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000073 in 1,588,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S778A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000722.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA2D1 | NM_000722.4 | c.2333C>T | p.Ser778Leu | missense_variant | 29/39 | ENST00000356860.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA2D1 | ENST00000356860.8 | c.2333C>T | p.Ser778Leu | missense_variant | 29/39 | 1 | NM_000722.4 |
Frequencies
GnomAD3 genomes AF: 0.0000800 AC: 12AN: 150042Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000563 AC: 14AN: 248874Hom.: 0 AF XY: 0.0000594 AC XY: 8AN XY: 134614
GnomAD4 exome AF: 0.0000723 AC: 104AN: 1438388Hom.: 0 Cov.: 26 AF XY: 0.0000698 AC XY: 50AN XY: 716824
GnomAD4 genome AF: 0.0000799 AC: 12AN: 150152Hom.: 0 Cov.: 32 AF XY: 0.0000546 AC XY: 4AN XY: 73236
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2017 | A variant of uncertain significance has been identified in the CACNA2D1 gene. The S778L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S778L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis suggests that this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 778 of the CACNA2D1 protein (p.Ser778Leu). This variant is present in population databases (rs202108848, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of CACNA2D1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 264556). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2021 | The p.S778L variant (also known as c.2333C>T), located in coding exon 29 of the CACNA2D1 gene, results from a C to T substitution at nucleotide position 2333. The serine at codon 778 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at