12-2053575-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_000719.7(CACNA1C):c.13A>C(p.Asn5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,650 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N5S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.13A>C | p.Asn5His | missense_variant | 1/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.13A>C | p.Asn5His | missense_variant | 1/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.13A>C | p.Asn5His | missense_variant | 1/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.13A>C | p.Asn5His | missense_variant | 1/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000276 AC: 4AN: 1448650Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 719244
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 5 of the CACNA1C protein (p.Asn5His). 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: 1439077). 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 with a negative predictive value of 95%. 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 07, 2023 | The p.N5H variant (also known as c.13A>C), located in coding exon 1 of the CACNA1C gene, results from an A to C substitution at nucleotide position 13. The asparagine at codon 5 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available 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