rs12131800

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_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

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

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]

CACNA1E links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 4 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 chr1-181724500-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3262735.Status of the report is criteria_provided_single_submitter, 1 stars.

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 rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 link	c.2104G>A	p.Ala702Thr	missense_variant	Exon 17 of 48	ENST00000367573.7	NP_001192222.1	Q15878-1Q59FG1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1E	ENST00000367573.7 link	c.2104G>A	p.Ala702Thr	missense_variant	Exon 17 of 48	1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 link	c.2104G>A	p.Ala702Thr	missense_variant	Exon 17 of 47	5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000367570.6 link	c.2104G>A	p.Ala702Thr	missense_variant	Exon 17 of 47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000621791.4 link	c.2104G>A	p.Ala702Thr	missense_variant	Exon 17 of 46	1		ENSP00000481619.1	Q15878-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000133

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 69

Pathogenic:7

Aug 08, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2,PP2,PP3 -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2020

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 06, 2023

Acibadem Labgen Genetic Diagnostic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 521483). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1E protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CACNA1E function (PMID: 30343943). For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published 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) -

Jun 15, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 07, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Nov 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Van der Woude syndrome 1

Pathogenic:1

Oct 28, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;.;.;D;D;.;D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D;.;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.;H;.;H;H;H

PrimateAI

Pathogenic

0.93

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over