rs1159957403

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001205293.3(CACNA1E):c.4777A>G(p.Ile1593Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,595,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1E
NM_001205293.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 8.76

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

PP5

Variant 1-181763493-A-G is Pathogenic according to our data. Variant chr1-181763493-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450052.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 link	c.4777A>G	p.Ile1593Val	missense_variant	Exon 34 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.4777A>G	p.Ile1593Val	missense_variant	Exon 34 of 48	1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 link	c.4720A>G	p.Ile1574Val	missense_variant	Exon 33 of 47	5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000367570.6 link	c.4777A>G	p.Ile1593Val	missense_variant	Exon 34 of 47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000621791.4 link	c.4720A>G	p.Ile1574Val	missense_variant	Exon 33 of 46	1		ENSP00000481619.1	Q15878-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443510

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33192

American (AMR)

AF:

0.00

AC:

AN:

44376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39224

South Asian (SAS)

AF:

0.00

AC:

AN:

85156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097540

Other (OTH)

AF:

0.00

AC:

AN:

59394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 12, 2018

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing;provider interpretation

This variant was identified in a 2 year old male with autism spectrum disorder, developmental delays, seizures, and wide-based gait. This variant is absent from the gnomAD database and computational models predict it to be damaging. The CACNA1E gene has yet to be clearly associated with a human disorder through multiple publications, although it has been suggested as a candidate gene for neurodevelopmental phenotypes (O'Roak, 2012; Helbig, 2016). It is also constrained for both missense and loss of function variation based on population data. The laboratory report indicates additional internal data which implicates this gene as causative for neurodevelopmental phenotypes; however, this is not yet publicly available. Therefore, although this is a highly suspicious variant, we consider this a variant of uncertain significance at this time. -

Nov 30, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30311381) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;.;.;D;T;.;D;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.75

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

M;.;.;M;.;M;M;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.96

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.015

D;.;T;D;.;.;.;.

Sift4G

Pathogenic

0.0

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

Polyphen

0.74

P;P;.;D;.;P;D;P

Vest4

0.67

MutPred

0.71

Loss of MoRF binding (P = 0.1289);.;.;Loss of MoRF binding (P = 0.1289);.;Loss of MoRF binding (P = 0.1289);Loss of MoRF binding (P = 0.1289);.;

MVP

0.96

MPC

1.3

ClinPred

0.96

GERP RS

5.3

Varity_R

0.22

gMVP

0.75

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over