rs187393245
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001127222.2(CACNA1A):c.3166C>T(p.Arg1056Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000341 in 1,613,484 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1056H) has been classified as Likely benign.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.3166C>T | p.Arg1056Cys | missense_variant | 20/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.3166C>T | p.Arg1056Cys | missense_variant | 20/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000269 AC: 66AN: 245698Hom.: 0 AF XY: 0.000224 AC XY: 30AN XY: 134156
GnomAD4 exome AF: 0.000355 AC: 519AN: 1461172Hom.: 8 Cov.: 35 AF XY: 0.000334 AC XY: 243AN XY: 726874
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152312Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16AN XY: 74474
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2016 | A variant of uncertain significance has been identified in the CACNA1A gene. The R1057C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports R1057C was observed in 4/208 (2.0%) alleles from individuals of Japanese background, indicating it may be a rare (benign) variant in this population. The R1057C 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 in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2017 | The p.R1057C variant (also known as c.3169C>T), located in coding exon 20 of the CACNA1A gene, results from a C to T substitution at nucleotide position 3169. The arginine at codon 1057 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at