rs786200963
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001127222.2(CACNA1A):c.631+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000000708 in 1,412,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001127222.2 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.631+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.631+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 7.08e-7 AC: 1AN: 1412862Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 698558
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 30, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2023 | Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37177896, 25735478, 33349592) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Episodic ataxia type 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | E. Rossignol Lab, CHU Ste-Justine, Universite de Montreal | Nov 25, 2014 | - - |
CACNA1A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 31, 2021 | The CACNA1A c.631+5G>A variant, also referred to as c.868+5G>A in the literature, is a splice region variant that has been reported in one study, in which it was identified in a proband with episodic ataxia type 2 and in his affected mother (Damaj et al. 2015). Another variant at the same nucleotide position has also been reported in two individuals with CACNA1A-related disorders (Gur-Hartman et al. 2021). The c.631+5G>A variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the c.631+5G>A variant is classified as likely pathogenic for CACNA1A-related disorders. - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 187829). This variant has been observed in individual(s) with episodic ataxia (Invitae). 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 falls in intron 4 of the CACNA1A gene. It does not directly change the encoded amino acid sequence of the CACNA1A protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at