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rs1553360130

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001205293.3(CACNA1E):c.6028G>A(p.Val2010Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,455,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA1E
NM_001205293.3 missense, splice_region

Scores

2
9
5
Splicing: ADA: 0.9776
1
1

Clinical Significance

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

Conservation

PhyloP100: 4.54
Variant links:
Genes affected
CACNA1E (HGNC:1392): (calcium voltage-gated channel subunit alpha1 E) Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These 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, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, CACNA1E

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ENM_001205293.3 linkuse as main transcriptc.6028G>A p.Val2010Met missense_variant, splice_region_variant 46/48 ENST00000367573.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1EENST00000367573.7 linkuse as main transcriptc.6028G>A p.Val2010Met missense_variant, splice_region_variant 46/481 NM_001205293.3 A2Q15878-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1455966
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
723990
show subpopulations
Gnomad4 AFR exome
AF:
0.0000603
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 GeneticsSep 21, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 06, 2024This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1967 of the CACNA1E protein (p.Val1967Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1E-related conditions. ClinVar contains an entry for this variant (Variation ID: 521249). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
Cadd
Pathogenic
27
Dann
Uncertain
0.98
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.91
D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.45
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.78
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.62
N;.;N;N;.;.;.;.
REVEL
Uncertain
0.48
Sift
Benign
0.21
T;.;T;T;.;.;.;.
Sift4G
Benign
0.28
T;T;T;T;T;T;T;T
Polyphen
0.99
D;B;.;.;.;D;.;B
Vest4
0.55
MutPred
0.22
Loss of stability (P = 0.065);.;.;.;.;Loss of stability (P = 0.065);.;.;
MVP
0.85
MPC
0.83
ClinPred
0.63
D
GERP RS
5.9
Varity_R
0.13
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Benign
0.71
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: rs1553360130; hg19: chr1-181764000; API