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rs12131800

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001205293.3(CACNA1E):c.2104G>A(p.Ala702Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A702S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1E
NM_001205293.3 missense

Scores

13
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.73
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 Pathogenic. Variant got 17 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001205293.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-181724499-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427007.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant where missense usually causes diseases, CACNA1E
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89
PP5
Variant 1-181724499-G-A is Pathogenic according to our data. Variant chr1-181724499-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-181724499-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ENM_001205293.3 linkuse as main transcriptc.2104G>A p.Ala702Thr missense_variant 17/48 ENST00000367573.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1EENST00000367573.7 linkuse as main transcriptc.2104G>A p.Ala702Thr missense_variant 17/481 NM_001205293.3 A2Q15878-1
CACNA1EENST00000367570.6 linkuse as main transcriptc.2104G>A p.Ala702Thr missense_variant 17/471 P4Q15878-3
CACNA1EENST00000621791.4 linkuse as main transcriptc.2104G>A p.Ala702Thr missense_variant 17/461 A2Q15878-2
CACNA1EENST00000360108.7 linkuse as main transcriptc.2104G>A p.Ala702Thr missense_variant 17/475 A2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.000133
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 69 Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingAcibadem Labgen Genetic Diagnostic CenterMar 06, 2023- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 18, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 20, 2021- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHFeb 06, 2020- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 01, 2022Published functional studies demonstrate that this variant negatively affects channel voltage-dependent activation and slows inactivation (Helbig et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31064215, 17660294, 23934111, 33746731, 31175295, 33726816, 30343943) -
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJun 15, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeAug 15, 2022For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1E function (PMID: 30343943). 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 CACNA1E protein function. ClinVar contains an entry for this variant (Variation ID: 521483). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 30343943). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 702 of the CACNA1E protein (p.Ala702Thr). -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 07, 2017- -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityNov 01, 2018- -
Van der Woude syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneOct 28, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
Cadd
Pathogenic
29
Dann
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H;.;H;.;H;H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-3.5
D;.;D;D;.;.;.;.
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D;.;D;D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;.;D;.;D
Vest4
0.87
MutPred
0.43
Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);
MVP
0.94
MPC
2.0
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.62
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs12131800; hg19: chr1-181693635; COSMIC: COSV62415002; API