Variant chr1-181483776-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001205293.3(CACNA1E):c.32G>T(p.Arg11Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1E
NM_001205293.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.41324586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1E	NM_001205293.3 linkuse as main transcript	c.32G>T	p.Arg11Met	missense_variant	1/48	ENST00000367573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1E	ENST00000367573.7 linkuse as main transcript	c.32G>T	p.Arg11Met	missense_variant	1/48	1	NM_001205293.3	A2	Q15878-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247904

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459248

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725772

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000372

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 69

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Uncertain

0.67

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

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

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

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.41

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

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.6

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

MutationTaster

Benign

1.0

D;D;D;N;N;N;N

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.56

Sift

Benign

0.034

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

Sift4G

Uncertain

0.031

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

Polyphen

0.058

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

Vest4

0.28, 0.31, 0.37, 0.39, 0.38, 0.36, 0.37, 0.41

MutPred

0.27

.;Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);Loss of MoRF binding (P = 0.0339);

MVP

0.91

MPC

1.8

ClinPred

0.73

GERP RS

5.3

Varity_R

0.16

gMVP

0.46

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