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rs1555732391

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001127222.2(CACNA1A):c.5891A>G(p.Tyr1964Cys) variant causes a missense 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

6
7
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.68
Variant links:
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, CACNA1A
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.5891A>G p.Tyr1964Cys missense_variant 40/47 ENST00000360228.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.5891A>G p.Tyr1964Cys missense_variant 40/471 NM_001127222.2 O00555-8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 08, 2022The c.5894A>G (p.Y1965C) alteration is located in coding exon 40 of the CACNA1A gene. This alteration results from an A to G substitution at nucleotide position 5894, causing the tyrosine (Y) at amino acid position 1965 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 27, 2023Not 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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.53
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
Sift4G
Uncertain
0.035
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.86
MutPred
0.73
.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);.;.;.;.;
MVP
0.84
MPC
0.96
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.83
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555732391; hg19: chr19-13325096; API