rs756734279
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_000719.7(CACNA1C):āc.3943A>Gā(p.Met1315Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000212 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000719.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.3943A>G | p.Met1315Val | missense_variant, splice_region_variant | 31/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.3943A>G | p.Met1315Val | missense_variant, splice_region_variant | 31/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.3943A>G | p.Met1315Val | missense_variant, splice_region_variant | 31/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.3943A>G | p.Met1315Val | missense_variant, splice_region_variant | 31/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249286Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135248
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461600Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727090
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 190615; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | 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. 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 CACNA1C protein function. ClinVar contains an entry for this variant (Variation ID: 190615). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (rs756734279, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1315 of the CACNA1C protein (p.Met1315Val). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2022 | The p.M1315V variant (also known as c.3943A>G), located in coding exon 31 of the CACNA1C gene, results from an A to G substitution at nucleotide position 3943. The methionine at codon 1315 is replaced by valine, an amino acid with highly similar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association of this alteration with CACNA1C-related long QT syndrome or Timothy syndrome is unlikely. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at