19-13303584-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001127222.2(CACNA1A):c.2134G>A(p.Ala712Thr) variant causes a missense change. 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 (★★).
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 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.2134G>A | p.Ala712Thr | missense_variant | Exon 17 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.2140G>A | p.Ala714Thr | missense_variant | Exon 17 of 47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.1996G>A | p.Ala666Thr | missense_variant | Exon 16 of 46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.2140G>A | p.Ala714Thr | missense_variant | Exon 17 of 47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.2137G>A | p.Ala713Thr | missense_variant | Exon 17 of 46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 42 Pathogenic:6
We consider the variant NM_001127221.2:c.2137G>A as disease-causing; it results in an amino acid substitution p.Ala713Thr. -
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A heterozygous missense variation in exon 17 of the CACNA1A gene that results in the amino acid substitution of Threonine for Alanine at codon 712 (p.Ala712Thr) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a Likely Pathogenic. -
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.75). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000254268). A different missense change at the same codon (p.Ala712Ser) has been reported to be associated with CACNA1A -related disorder (ClinVar ID: VCV000997449). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
The CACNA1A c.2137G>A (p.Ala713Thr) variant is a missense variant that has been reported in a heterozygous, de novo state in at least three unrelated individuals with epilepsy syndromes (Epi4K Consortium, Epilepsy Phenome/Genome Project 2013; Epi4K Consortium 2016; Balck et al. 2017). It was also identified in a fourth individual with seizures who had a similarly affected sibling. In this case, the variant was inherited from an unaffected parent who was mosaic for the variant with 6% mutational load in lymphocyte-derived DNA (Balck et al. 2017). In addition to early onset of multiple seizure types, individuals with this variant also showed abnormal movements in utero, ataxic movements and gait, mild dysmetria, dystonic posturing, and developmental delay/intellectual disability. The p.Ala713Thr variant is not found in the Genome Aggregation Database in a region of good sequencing coverage. Based on the collective evidence, the p.Ala713Thr variant is classified as pathogenic for early infantile epileptic encephalopathy. -
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Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 713 of the CACNA1A protein (p.Ala713Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 23934111, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254268). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
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Abnormality of the nervous system Pathogenic:1
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not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27476654, 29186148, 23934111, 28488083, 26633542, 28455667, 31175295, 33425808, 29100083, 31468518, 32005694, 34102571, 34263451) -
Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1
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Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
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Familial hemiplegic migraine;C1720416:Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Other:1
Variant interpreted as Likely pathogenic and reported on 08-12-2015 by lab or GTR ID 61756. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IIDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at