rs704326

Positions:

chr1-181790521-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. A1955A) has been classified as Likely benign.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

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 id 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/exons	MANE	UniProt
CACNA1E	NM_001205293.3 linkuse as main transcript	c.5863G>A	p.Ala1955Thr	missense_variant	44/48	ENST00000367573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1E	ENST00000367573.7 linkuse as main transcript	c.5863G>A	p.Ala1955Thr	missense_variant	44/48	1	NM_001205293.3	A2	Q15878-1
CACNA1E	ENST00000367570.6 linkuse as main transcript	c.5863G>A	p.Ala1955Thr	missense_variant	44/47	1		P4	Q15878-3
CACNA1E	ENST00000621791.4 linkuse as main transcript	c.5806G>A	p.Ala1936Thr	missense_variant	43/46	1		A2	Q15878-2
CACNA1E	ENST00000360108.7 linkuse as main transcript	c.5806G>A	p.Ala1936Thr	missense_variant	43/47	5		A2

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

GnomAD3 exomes

AF:

0.388

AC:

96763

AN:

249132

Hom.:

20201

AF XY:

0.389

AC XY:

52582

AN XY:

135166

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 SAS exome

AF:

0.221

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

Gnomad4 AFR exome

AF:

0.139

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.498

Gnomad4 EAS exome

AF:

0.420

Gnomad4 SAS exome

AF:

0.226

Gnomad4 FIN exome

AF:

0.448

Gnomad4 NFE exome

AF:

0.462

Gnomad4 OTH exome

AF:

0.409

GnomAD4 genome

AF:

0.357

AC:

54219

AN:

151956

Hom.:

11150

Cov.:

AF XY:

0.354

AC XY:

26273

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.360

Gnomad4 ASJ

AF:

0.510

Gnomad4 EAS

AF:

0.408

Gnomad4 SAS

AF:

0.218

Gnomad4 FIN

AF:

0.441

Gnomad4 NFE

AF:

0.464

Gnomad4 OTH

AF:

0.356

Alfa

AF:

0.440

Hom.:

39844

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Developmental and epileptic encephalopathy, 69

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

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;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

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

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

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