rs554393704
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001127222.2(CACNA1A):c.6466C>T(p.Arg2156Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,395,708 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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CACNA1A | ENST00000360228.11 | c.6466C>T | p.Arg2156Cys | missense_variant | Exon 45 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.6484C>T | p.Arg2162Cys | missense_variant | Exon 46 of 48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.6472C>T | p.Arg2158Cys | missense_variant | Exon 45 of 47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.6469C>T | p.Arg2157Cys | missense_variant | Exon 45 of 47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.6469C>T | p.Arg2157Cys | missense_variant | Exon 45 of 47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.6433C>T | p.Arg2145Cys | missense_variant | Exon 44 of 46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.6328C>T | p.Arg2110Cys | missense_variant | Exon 44 of 46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.6469C>T | p.Arg2157Cys | missense_variant | Exon 45 of 47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.6484C>T | p.Arg2162Cys | missense_variant | Exon 46 of 48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.6475C>T | p.Arg2159Cys | missense_variant | Exon 46 of 48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.6472C>T | p.Arg2158Cys | missense_variant | Exon 45 of 47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.6469C>T | p.Arg2157Cys | missense_variant | Exon 45 of 47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.6469C>T | p.Arg2157Cys | missense_variant | Exon 45 of 47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.6433C>T | p.Arg2145Cys | missense_variant | Exon 44 of 46 | 5 | ENSP00000489777.1 | |||
CACNA1A | ENST00000636768.1 | n.*732C>T | non_coding_transcript_exon_variant | Exon 9 of 10 | 5 | ENSP00000490190.2 | ||||
CACNA1A | ENST00000636768.1 | n.*732C>T | 3_prime_UTR_variant | Exon 9 of 10 | 5 | ENSP00000490190.2 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000299 AC: 15AN: 50246Hom.: 0 AF XY: 0.000392 AC XY: 10AN XY: 25528
GnomAD4 exome AF: 0.000106 AC: 132AN: 1243424Hom.: 2 Cov.: 32 AF XY: 0.000165 AC XY: 99AN XY: 600646
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74466
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
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Inborn genetic diseases Uncertain:1
The p.R2157C variant (also known as c.6469C>T), located in coding exon 45 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6469. The arginine at codon 2157 is replaced by cysteine, an amino acid with highly dissimilar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
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Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
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CACNA1A-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at