1-181483787-G-A

Position:

chr1-181483787-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001205293.3(CACNA1E):c.43G>A(p.Gly15Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,611,768 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CACNA1E
NM_001205293.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.21

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:

CACNA1E (HGNC:):

CACNA1E links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.754

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 linkuse as main transcript	c.43G>A	p.Gly15Ser	missense_variant	1/48	ENST00000367573.7	NP_001192222.1	Q15878-1Q59FG1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1E	ENST00000367573.7 linkuse as main transcript	c.43G>A	p.Gly15Ser	missense_variant	1/48	1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 linkuse as main transcript	c.43G>A	p.Gly15Ser	missense_variant	1/47	5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000367570.6 linkuse as main transcript	c.43G>A	p.Gly15Ser	missense_variant	1/47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000621791.4 linkuse as main transcript	c.43G>A	p.Gly15Ser	missense_variant	1/46	1		ENSP00000481619.1	Q15878-2
CACNA1E	ENST00000524607.6 linkuse as main transcript	c.478G>A	p.Gly160Ser	missense_variant	3/12	5		ENSP00000432038.2	E9PIE8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151568

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00000479

AC:

AN:

1460200

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151568

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73980

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1E-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 15 of the CACNA1E protein (p.Gly15Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

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

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.75

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

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.53

Sift

Benign

0.067

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

Sift4G

Benign

0.067

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

Polyphen

0.93

.;P;.;.;.;.;P;.;.

Vest4

0.34, 0.34, 0.52, 0.54, 0.42, 0.47, 0.52

MVP

0.86

MPC

2.1

ClinPred

0.96

GERP RS

5.3

Varity_R

0.26

gMVP

0.44

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