rs371273055
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_001127222.2(CACNA1A):c.5095G>C(p.Ala1699Pro) 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
CACNA1A
NM_001127222.2 missense
NM_001127222.2 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 7.86
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_001127222.2
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1A | ENST00000360228.11 | c.5095G>C | p.Ala1699Pro | missense_variant | Exon 33 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
| CACNA1A | ENST00000638029.1 | c.5113G>C | p.Ala1705Pro | missense_variant | Exon 34 of 48 | 5 | ENSP00000489829.1 | |||
| CACNA1A | ENST00000573710.7 | c.5101G>C | p.Ala1701Pro | missense_variant | Exon 33 of 47 | 5 | ENSP00000460092.3 | |||
| CACNA1A | ENST00000635727.1 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 47 | 5 | ENSP00000490001.1 | |||
| CACNA1A | ENST00000637769.1 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 47 | 1 | ENSP00000489778.1 | |||
| CACNA1A | ENST00000636012.1 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 46 | 5 | ENSP00000490223.1 | |||
| CACNA1A | ENST00000637736.1 | c.4957G>C | p.Ala1653Pro | missense_variant | Exon 32 of 46 | 5 | ENSP00000489861.1 | |||
| CACNA1A | ENST00000636389.1 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 47 | 5 | ENSP00000489992.1 | |||
| CACNA1A | ENST00000637432.1 | c.5113G>C | p.Ala1705Pro | missense_variant | Exon 34 of 48 | 5 | ENSP00000490617.1 | |||
| CACNA1A | ENST00000636549.1 | c.5104G>C | p.Ala1702Pro | missense_variant | Exon 34 of 48 | 5 | ENSP00000490578.1 | |||
| CACNA1A | ENST00000637927.1 | c.5101G>C | p.Ala1701Pro | missense_variant | Exon 33 of 47 | 5 | ENSP00000489715.1 | |||
| CACNA1A | ENST00000635895.1 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 47 | 5 | ENSP00000490323.1 | |||
| CACNA1A | ENST00000638009.2 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 47 | 1 | ENSP00000489913.1 | |||
| CACNA1A | ENST00000637276.1 | c.5098G>C | p.Ala1700Pro | missense_variant | Exon 33 of 46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
Sep 21, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 1700 of the CACNA1A protein (p.Ala1700Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;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;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
0.84
.;.;Loss of catalytic residue at A1700 (P = 0.0969);Loss of catalytic residue at A1700 (P = 0.0969);Loss of catalytic residue at A1700 (P = 0.0969);.;.;Loss of catalytic residue at A1700 (P = 0.0969);.;.;.;Loss of catalytic residue at A1700 (P = 0.0969);Loss of catalytic residue at A1700 (P = 0.0969);.;Loss of catalytic residue at A1700 (P = 0.0969);.;.;.;.;
MVP
MPC
2.7
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
Publications
No publications associated with this variant yet.