rs1057518456
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_000719.7(CACNA1C):āc.130C>Gā(p.Pro44Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000502 in 1,594,066 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 Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. P44P) has been classified as Likely benign.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.130C>G | p.Pro44Ala | missense_variant | 2/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.130C>G | p.Pro44Ala | missense_variant | 2/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.130C>G | p.Pro44Ala | missense_variant | 2/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.130C>G | p.Pro44Ala | missense_variant | 2/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000416 AC: 6AN: 1441832Hom.: 0 Cov.: 32 AF XY: 0.00000559 AC XY: 4AN XY: 715902
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74380
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2016 | The P44A variant in the CACNA1C gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P44A variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P44A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P44A as a variant of uncertain significance. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Oct 01, 2016 | Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 20, 2022 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the CACNA1C protein (p.Pro44Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 373514). 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. 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 19, 2023 | The p.P44A variant (also known as c.130C>G), located in coding exon 2 of the CACNA1C gene, results from a C to G substitution at nucleotide position 130. The proline at codon 44 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at