rs12131800

Positions:

• chr1-181724499-G-A
• chr1-181724499-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001205293.3(CACNA1E):​c.2104G>A​(p.Ala702Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A702P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.73

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a repeat II (size 244) in uniprot entity CAC1E_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001205293.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.89
• PP5: Variant 1-181724499-G-A is Pathogenic according to our data. Variant chr1-181724499-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-181724499-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.2104G>A	p.Ala702Thr	missense_variant	17/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.2104G>A	p.Ala702Thr	missense_variant	17/48	1	NM_001205293.3	ENSP00000356545	A2
CACNA1E	ENST00000367570.6	c.2104G>A	p.Ala702Thr	missense_variant	17/47	1		ENSP00000356542	P4
CACNA1E	ENST00000621791.4	c.2104G>A	p.Ala702Thr	missense_variant	17/46	1		ENSP00000481619	A2
CACNA1E	ENST00000360108.7	c.2104G>A	p.Ala702Thr	missense_variant	17/47	5		ENSP00000353222	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.000133 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 69 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 18, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Feb 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Acibadem Labgen Genetic Diagnostic Center	Mar 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 08, 2024	Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2,PP2,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	Published functional studies demonstrate that this variant negatively affects channel voltage-dependent activation and slows inactivation (Helbig et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31064215, 17660294, 23934111, 33746731, 31175295, 33726816, 30343943) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1E function (PMID: 30343943). 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) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1E protein function. ClinVar contains an entry for this variant (Variation ID: 521483). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 30343943). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 702 of the CACNA1E protein (p.Ala702Thr). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2017

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 01, 2018

- -

Van der Woude syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;D;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;.;H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.;D
Vest4		0.87
MutPred		0.43		Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);Gain of glycosylation at A702 (P = 0.0547);
MVP		0.94
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.62
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12131800; hg19: chr1-181693635; COSMIC: COSV62415002;