rs1271930393
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_001127222.2(CACNA1A):c.4448G>T(p.Arg1483Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CACNA1A
NM_001127222.2 missense
NM_001127222.2 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 7.84
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 7 ACMG points.
PM1
In a repeat III (size 283) 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 gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ: 5.7845 (greater than the threshold 3.09). Trascript score misZ: 3.9354 (greater than threshold 3.09). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the gene with 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, 0.904
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.4448G>T | p.Arg1483Leu | missense_variant | 28/47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.4460G>T | p.Arg1487Leu | missense_variant | 28/48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.4454G>T | p.Arg1485Leu | missense_variant | 28/47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.4310G>T | p.Arg1437Leu | missense_variant | 27/46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.4460G>T | p.Arg1487Leu | missense_variant | 28/48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.4454G>T | p.Arg1485Leu | missense_variant | 28/47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.4451G>T | p.Arg1484Leu | missense_variant | 28/46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 07, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;.;.;.;.;.;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
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;M;.;.;.;.;.;.;.;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
0.59
.;.;Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);.;Loss of disorder (P = 0.0319);.;.;Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);.;Loss of disorder (P = 0.0319);.;Loss of disorder (P = 0.0319);.;
MVP
MPC
2.6
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