rs869312920

Positions:

• chr1-181724488-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The ENST00000367573.7(CACNA1E):​c.2093T>C​(p.Phe698Ser) 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. 12/21 in silico tools predict a damaging 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. F698L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1E ENST00000367573.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.80

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000367573.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-181724489-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 870847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.968
• PP5: Variant 1-181724488-T-C is Pathogenic according to our data. Variant chr1-181724488-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224995.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-181724488-T-C is described in Lovd as [Pathogenic]. Variant chr1-181724488-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.2093T>C	p.Phe698Ser	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.2093T>C	p.Phe698Ser	missense_variant	17/48	1	NM_001205293.3	ENSP00000356545	A2
CACNA1E	ENST00000367570.6	c.2093T>C	p.Phe698Ser	missense_variant	17/47	1		ENSP00000356542	P4
CACNA1E	ENST00000621791.4	c.2093T>C	p.Phe698Ser	missense_variant	17/46	1		ENSP00000481619	A2
CACNA1E	ENST00000360108.7	c.2093T>C	p.Phe698Ser	missense_variant	17/47	5		ENSP00000353222	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2013

- -

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

- -

Developmental and epileptic encephalopathy, 69 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;.;H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.8	D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.;D
Vest4		0.97
MutPred		0.79		Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);Loss of stability (P = 0.0393);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.98

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: rs869312920; hg19: chr1-181693624;