rs535350857
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_000719.7(CACNA1C):c.5600G>A(p.Arg1867Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,718 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. R1867W) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5600G>A | p.Arg1867Gln | missense_variant | 44/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5600G>A | p.Arg1867Gln | missense_variant | 44/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.333+4378C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5600G>A | p.Arg1867Gln | missense_variant | 44/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5600G>A | p.Arg1867Gln | missense_variant | 44/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.294+4378C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 248922Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135052
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727000
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74458
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1867 of the CACNA1C protein (p.Arg1867Gln). This variant is present in population databases (rs535350857, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 518667). 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 | Nov 21, 2023 | The p.R1867Q variant (also known as c.5600G>A), located in coding exon 44 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5600. The arginine at codon 1867 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Timothy syndrome or long QT syndrome; however, its contribution to the development of CACNA1C-related neurodevelopmental disorder is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at