chr19-13255217-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001127222.2(CACNA1A):c.4633C>T(p.Arg1545*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001127222.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.4633C>T | p.Arg1545* | stop_gained | Exon 29 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.4645C>T | p.Arg1549* | stop_gained | Exon 29 of 48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.4639C>T | p.Arg1547* | stop_gained | Exon 29 of 47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.4495C>T | p.Arg1499* | stop_gained | Exon 28 of 46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.4645C>T | p.Arg1549* | stop_gained | Exon 29 of 48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.4639C>T | p.Arg1547* | stop_gained | Exon 29 of 47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.4636C>T | p.Arg1546* | stop_gained | Exon 29 of 46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Episodic ataxia type 2 Pathogenic:4
This variant is interpreted as Likely Pathogenic, for Episodic ataxia 2, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1-Moderate => PP1 upgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/10408533). -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with CACNA1A-related disease. Episodic ataxia, type 2 (MIM#108500) is caused by variants with a loss of function mechanism (PMID: 28566750). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for patients with episodic ataxia type 2 (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Two families with episodic ataxia, intellectual disability and/or epilepsy have been reported with intrafamilial variability (PMID: 32910250, PMID: 30142438). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported in patients with episodic ataxia type 2 (ClinVar, PMID: 10408533, PMID: 29883219). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
ACMG codes: PVS1, PS3, PM2, PP5 -
not provided Pathogenic:2
Described as R1549X and R1547X using alternate nomenclature, published functional studies demonstrate markedly decreased current densities compared to wild type (Jen et al., 2001; Jeng et al., 2006); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10408533, 29062094, 29482223, 16306128, 25525159, 29883219, 11723274) -
This variant segregates with episodic ataxia in at least one family. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as p.R1549X. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant diminished calcium channel activity (PMID: 11723274, 16306128). -
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg1546*) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CACNA1A-related conditions (PMID: 29062094, 29883219, 31302675). This variant is also known as p.Arg1549*. ClinVar contains an entry for this variant (Variation ID: 8507). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CACNA1A function (PMID: 11723274). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases 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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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at