rs1555745461
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.4072C>T(p.Arg1358Trp) variant causes a missense change. 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. R1358Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CACNA1A
NM_001127222.2 missense
NM_001127222.2 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 4.83
Genes affected
CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001127222.2
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr19-13262750-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2924641.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, CACNA1A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.941
PP5
?
Variant 19-13262751-G-A is Pathogenic according to our data. Variant chr19-13262751-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13262751-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.4072C>T | p.Arg1358Trp | missense_variant | 25/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.4072C>T | p.Arg1358Trp | missense_variant | 25/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459360Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726020
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1459360
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
726020
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 22, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2022 | Not observed 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: 24091540, 26863999, 31618753) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 22, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging. - |
CACNA1A-associated disorders Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Program, Stanford Medicine | May 24, 2019 | The p.Arg1359Trp variant in the CACNA1A gene has been previously reported de novo in two unrelated individuals, one individual with early onset epilepsy, ataxia, dysmetria, oculomotor apraxia, tremor, developmental delay, intellectual disability, speech delay, hypotonia, and pyramidal sign (Ohba et al., 2013), and one individual with an undescribed neurological condition (Nolan and Carlson, 2015). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CACNA1A gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Arg1359Trp variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg1359Trp variant as likely pathogenic for CACNA1A-assocatied disorders in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2; PM2; PP2; PP3] - |
Delayed gross motor development Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
0.72
.;.;Loss of phosphorylation at T1356 (P = 0.0773);Loss of phosphorylation at T1356 (P = 0.0773);Loss of phosphorylation at T1356 (P = 0.0773);.;Loss of phosphorylation at T1356 (P = 0.0773);.;.;Loss of phosphorylation at T1356 (P = 0.0773);Loss of phosphorylation at T1356 (P = 0.0773);.;Loss of phosphorylation at T1356 (P = 0.0773);.;Loss of phosphorylation at T1356 (P = 0.0773);
MVP
MPC
2.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at