1-181483797-A-G

Position:

• chr1-181483797-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001205293.3(CACNA1E):​c.53A>G​(p.Asp18Gly) 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. 12/21 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.18

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.10491052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.53A>G	p.Asp18Gly	missense_variant	1/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.53A>G	p.Asp18Gly	missense_variant	1/48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.53A>G	p.Asp18Gly	missense_variant	1/47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.53A>G	p.Asp18Gly	missense_variant	1/47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.53A>G	p.Asp18Gly	missense_variant	1/46	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.488A>G	p.Asp163Gly	missense_variant	3/12	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 28, 2022	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. 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. 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). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 18 of the CACNA1E protein (p.Asp18Gly). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.46
DEOGEN2	Benign	0.10	.;.;.;.;T;T;.;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.87	D;.;.;D;.;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	-0.48	.;N;N;.;N;.;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	1.8	.;N;.;N;N;.;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.97	.;T;.;T;T;.;.;.;.
Sift4G	Benign	1.0	.;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.;B;.;.
Vest4		0.062, 0.090, 0.14, 0.15, 0.14, 0.17, 0.14
MutPred		0.15		.;Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);Gain of MoRF binding (P = 0.0672);
MVP		0.81
MPC		2.0
ClinPred		0.52	D
GERP RS		5.3
Varity_R		0.098
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-181452933;