1-181483804-C-A

Variant names:

• chr1-181483804-C-A
• NM_001205293.3:c.60C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001205293.3(CACNA1E):​c.60C>A​(p.Asp20Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.553
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088499635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.60C>A	p.Asp20Glu	missense_variant	Exon 1 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.60C>A	p.Asp20Glu	missense_variant	Exon 1 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.60C>A	p.Asp20Glu	missense_variant	Exon 1 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.60C>A	p.Asp20Glu	missense_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.60C>A	p.Asp20Glu	missense_variant	Exon 1 of 46	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.495C>A	p.Asp165Glu	missense_variant	Exon 3 of 12	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 20 of the CACNA1E protein (p.Asp20Glu). 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CACNA1E-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.65
DEOGEN2	Benign	0.13	.;.;.;.;T;T;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T;.;.;T;.;T;T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.088	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-1.2	.;N;N;.;N;.;N;N;N
PhyloP100		0.55
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.22	.;N;.;N;N;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	1.0	.;T;.;T;T;.;.;.;.
Sift4G	Benign	0.67	.;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.;B;.;.
Vest4		0.074, 0.095, 0.10, 0.13, 0.12, 0.13, 0.11, 0.16
MutPred		0.14		.;Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);Gain of glycosylation at S22 (P = 0.1716);
MVP		0.68
MPC		1.5
ClinPred		0.11	T
GERP RS		2.0
PromoterAI		-0.017	Neutral
Varity_R		0.070
gMVP		0.18
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

hg19: chr1-181452940;