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rs1361083258

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_001205293.3(CACNA1E):c.2069G>A(p.Gly690Asp) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G690V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1E
NM_001205293.3 missense

Scores

13
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 8.02
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 11 ACMG points.

PM1
In a transmembrane_region Helical; Name=S6 of repeat II (size 24) in uniprot entity CAC1E_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) 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 chr1-181721870-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1346057.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, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1ENM_001205293.3 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/48 ENST00000367573.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1EENST00000367573.7 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/481 NM_001205293.3 A2Q15878-1
CACNA1EENST00000367570.6 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/471 P4Q15878-3
CACNA1EENST00000621791.4 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/461 A2Q15878-2
CACNA1EENST00000360108.7 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/475 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityNov 01, 2018- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 05, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.6
H;H;.;H;.;H;H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-6.1
D;.;D;D;.;.;.;.
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0050
D;.;D;D;.;.;.;.
Sift4G
Uncertain
0.0060
D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;.;D;.;D
Vest4
0.85
MutPred
0.88
Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);
MVP
0.99
MPC
1.3
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.79
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1361083258; hg19: chr1-181691006; COSMIC: COSV100701379; API