rs1555558553
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_018896.5(CACNA1G):c.4591A>G(p.Met1531Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_018896.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1G | ENST00000359106.10 | c.4591A>G | p.Met1531Val | missense_variant | Exon 25 of 38 | 1 | NM_018896.5 | ENSP00000352011.5 | ||
CACNA1G | ENST00000507510.6 | c.4591A>G | p.Met1531Val | missense_variant | Exon 25 of 37 | 1 | ENSP00000423112.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits Pathogenic:2
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established however both loss- and gain-of-function have been reported (PMID: 31217264). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine (exon 25). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0603 - Missense variant located within the transmembrane S6 of repeat III in a region that is highly intolerant to missense variation (high constraint region). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in 3 patients with early onset CACNA1G-related disorders (PMID: 31836334; 29878067; 30792901) (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies demonstrated altered electrophysiological behaviour and increased calcium influx (PMID: 29878067) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at