rs1555740805
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.4897G>A(p.Asp1633Asn) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1633E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.4897G>A | p.Asp1633Asn | missense_variant | 31/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.4897G>A | p.Asp1633Asn | missense_variant | 31/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Episodic ataxia type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2024 | The c.4900G>A (p.D1634N) alteration is located in coding exon 31 of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4900, causing the aspartic acid (D) at amino acid position 1634 to be replaced by an asparagine (N). ; however, it is unlikely to be causative of CACN1A-related spinocerebellar ataxia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or reported as heterozygous in multiple individuals with features consistent with episodic ataxia, type 2 and CACNA1A-related neurologic disorders (Galatolo, 2021; Courage, 2021; Lipman, 2022; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31785789, 29165669, 19344873, 33798445, 34445196) - |
Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Wendy Chung Laboratory, Columbia University Medical Center | Mar 20, 2022 | - - |
CACNA1A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 24, 2020 | The CACNA1A c.4900G>A (p.Asp1634Asn) variant is a missense variant. It is reported as a de novo variant, though without confirmed parentage, in one individual in the DECIPHER database (Firth et al. 2009, patient 259278). The reported phenotype of this individual is consistent with CACNA1A-related disorders and includes global developmental delay, intellectual disability, sleep disturbance, unsteady gait, falls, behavioral abnormalities, brachycephaly, strabismus, and bilateral single transverse palmar creases. The p.Asp1634Asn variant has also been identified by clinical laboratories in individuals with neurodevelopmental phenotypes consistent with CACNA1A-related disorders and submitted to the ClinVar database (Landrum et al. 2018); however these cases are not reported in the published literature and clinical details are limited. This variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. The p.Asp1634Asn variant occurs at a conserved residue in the S3 transmembrane segment of domain IV of the voltage-dependent P/Q-type calcium channel subunit alpha-1A protein, though the function of this region is unknown. In silico predictions suggest a damaging consequence, however this has not been evaluated experimentally. Based on the collective evidence and the application of ACMG criteria, the p.Asp1634Asn variant is classified as likely pathogenic for CACNA1A-related disorders. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at