chr1-181483758-G-A

Position:

• chr1-181483758-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_001205293.3(CACNA1E):​c.14G>A​(p.Gly5Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,232 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94

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]

ACMG classification

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, 0.791
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1E	NM_001205293.3	c.14G>A	p.Gly5Glu	missense_variant	1/48	ENST00000367573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1E	ENST00000367573.7	c.14G>A	p.Gly5Glu	missense_variant	1/48	1	NM_001205293.3	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457232 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724708

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: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 10, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 5 of the CACNA1E protein (p.Gly5Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1E-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1E protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;.;.;.;D;T;.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;L;L;.;L;.;L;L;L
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	.;D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.099	.;T;.;T;T;.;.;.;.
Sift4G	Uncertain	0.045	.;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;D;.;.
Vest4		0.65, 0.64, 0.68, 0.66, 0.63, 0.66, 0.69, 0.63
MutPred		0.42		.;Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);
MVP		0.77
MPC		2.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.49
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs1663514169; hg19: chr1-181452894;