rs1361083258

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_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. 12/21 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

CACNA1E
NM_001205293.3 missense

Scores

15
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 Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a repeat II (size 244) in uniprot entity CAC1E_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001205293.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1E. . Gene score misZ 5.8125 (greater than the threshold 3.09). Trascript score misZ 6.7013 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 69.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1ENM_001205293.3 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/48 ENST00000367573.7 NP_001192222.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1EENST00000367573.7 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/481 NM_001205293.3 ENSP00000356545 A2Q15878-1
CACNA1EENST00000367570.6 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/471 ENSP00000356542 P4Q15878-3
CACNA1EENST00000621791.4 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/461 ENSP00000481619 A2Q15878-2
CACNA1EENST00000360108.7 linkuse as main transcriptc.2069G>A p.Gly690Asp missense_variant 16/475 ENSP00000353222 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
DEOGEN2
Pathogenic
0.99
.;.;.;D;D;.;D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;.;D;.;D;D;D;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