rs12131800

Variant names:

• chr1-181724499-G-A
• rs12131800
• NM_001205293.3:c.2104G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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. A702V) 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
• Publications: 11 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: Pathogenic. The variant received 16 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 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 chr1-181724500-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 931757.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 521483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.2104G>A	p.Ala702Thr	missense	Exon 17 of 48	NP_001192222.1
	CACNA1E	NM_000721.4		c.2104G>A	p.Ala702Thr	missense	Exon 17 of 47	NP_000712.2
	CACNA1E	NM_001205294.2		c.2104G>A	p.Ala702Thr	missense	Exon 17 of 46	NP_001192223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.2104G>A	p.Ala702Thr	missense	Exon 17 of 48	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.2104G>A	p.Ala702Thr	missense	Exon 17 of 47	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.2104G>A	p.Ala702Thr	missense	Exon 17 of 47	ENSP00000356542.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.000133 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Developmental and epileptic encephalopathy, 69 (7)
3	-	-	not provided (3)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Van der Woude syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.43		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs12131800; hg19: chr1-181693635; COSMIC: COSV62415002;