chr19-13359680-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.904G>A(p.Asp302Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D302G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.904G>A | p.Asp302Asn | missense_variant | 6/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.904G>A | p.Asp302Asn | missense_variant | 6/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455160Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723064
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 216896); This variant is associated with the following publications: (PMID: 27066515, 25326637, 27871455, 24486772) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | CACNA1A: PM2, PP4:Moderate, PS4:Moderate, PP2, PP3 - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 216896). This missense change has been observed in individuals with episodic ataxia 2 (PMID: 24486772, 25326637, 27066515, 27871455). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 302 of the CACNA1A protein (p.Asp302Asn). - |
Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Sep 09, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at