rs704326

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001205293.3(CACNA1E):c.5863G>A(p.Ala1955Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,608,712 control chromosomes in the GnomAD database, including 152,777 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1955P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.36 ( 11150 hom., cov: 31)

Exomes 𝑓: 0.43 ( 141627 hom. )

Consequence

CACNA1E
NM_001205293.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.366

Publications

41 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 69
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

CACNA1E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3509393E-4).

BP6

Variant 1-181790521-G-A is Benign according to our data. Variant chr1-181790521-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 link	c.5863G>A	p.Ala1955Thr	missense_variant	Exon 44 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.5863G>A	p.Ala1955Thr	missense_variant	Exon 44 of 48	1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 link	c.5806G>A	p.Ala1936Thr	missense_variant	Exon 43 of 47	5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000367570.6 link	c.5863G>A	p.Ala1955Thr	missense_variant	Exon 44 of 47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000621791.4 link	c.5806G>A	p.Ala1936Thr	missense_variant	Exon 43 of 46	1		ENSP00000481619.1	Q15878-2

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54185

AN:

151838

Hom.:

11138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.360

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.408

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.352

GnomAD2 exomes

AF:

0.388

AC:

96763

AN:

249132

AF XY:

0.389

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.337

Gnomad ASJ exome

AF:

0.494

Gnomad EAS exome

AF:

0.385

Gnomad FIN exome

AF:

0.442

Gnomad NFE exome

AF:

0.463

Gnomad OTH exome

AF:

0.405

GnomAD4 exome

AF:

0.433

AC:

630471

AN:

1456756

Hom.:

141627

Cov.:

AF XY:

0.428

AC XY:

310372

AN XY:

725032

show subpopulations

African (AFR)

AF:

0.139

AC:

4649

AN:

33420

American (AMR)

AF:

0.336

AC:

15034

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.498

AC:

12992

AN:

26100

East Asian (EAS)

AF:

0.420

AC:

16651

AN:

39674

South Asian (SAS)

AF:

0.226

AC:

19455

AN:

86158

European-Finnish (FIN)

AF:

0.448

AC:

23910

AN:

53386

Middle Eastern (MID)

AF:

0.333

AC:

1920

AN:

5758

European-Non Finnish (NFE)

AF:

0.462

AC:

511202

AN:

1107306

Other (OTH)

AF:

0.409

AC:

24658

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

15775

31549

47324

63098

78873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14956

29912

44868

59824

74780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.357

AC:

54219

AN:

151956

Hom.:

11150

Cov.:

AF XY:

0.354

AC XY:

26273

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.154

AC:

6387

AN:

41464

American (AMR)

AF:

0.360

AC:

5499

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1767

AN:

3466

East Asian (EAS)

AF:

0.408

AC:

2107

AN:

5160

South Asian (SAS)

AF:

0.218

AC:

1050

AN:

4806

European-Finnish (FIN)

AF:

0.441

AC:

4647

AN:

10536

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.464

AC:

31535

AN:

67928

Other (OTH)

AF:

0.356

AC:

750

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1644

3289

4933

6578

8222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.431

Hom.:

71928

Bravo

AF:

0.342

TwinsUK

AF:

0.456

AC:

1690

ALSPAC

AF:

0.455

AC:

1752

ESP6500AA

AF:

0.155

AC:

591

ESP6500EA

AF:

0.455

AC:

3736

ExAC

AF:

0.386

AC:

46587

Asia WGS

AF:

0.286

AC:

997

AN:

3478

EpiCase

AF:

0.453

EpiControl

AF:

0.458

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 31, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 69

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

5.9

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.11

.;.;.;T;T;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.61

.;.;T;.;T;T;T;T

MetaRNN

Benign

0.00014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

L;.;.;L;.;L;L;.

PhyloP100

0.37

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.38

N;.;N;N;.;.;.;.

REVEL

Benign

0.25

Sift

Benign

0.68

T;.;T;T;.;.;.;.

Sift4G

Benign

0.59

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;.;B;.;B

Vest4

0.050

MPC

0.25

ClinPred

0.00030

GERP RS

-1.5

Varity_R

0.025

gMVP

0.31

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over