chr1-181483778-C-T

Variant names:

• chr1-181483778-C-T
• NM_001205293.3:c.34C>T

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.34C>T​(p.Pro12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P12P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.653
• 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=0.14114398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.34C>T	p.Pro12Ser	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.34C>T	p.Pro12Ser	missense_variant	Exon 1 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.34C>T	p.Pro12Ser	missense_variant	Exon 1 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.34C>T	p.Pro12Ser	missense_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.34C>T	p.Pro12Ser	missense_variant	Exon 1 of 46	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.469C>T	p.Pro157Ser	missense_variant	Exon 3 of 12	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459182 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725804

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110792

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>T (p.P12S) alteration is located in exon 1 (coding exon 1) of the CACNA1E gene. This alteration results from a C to T substitution at nucleotide position 34, causing the proline (P) at amino acid position 12 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.13	.;.;.;.;T;T;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.89	D;.;.;D;.;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.024	D
MutationAssessor	Benign	0.63	.;N;N;.;N;.;N;N;N
PhyloP100		0.65
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.83	.;N;.;N;N;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.49	.;T;.;T;T;.;.;.;.
Sift4G	Benign	0.56	.;T;T;T;T;T;T;T;T
Polyphen		0.034	.;B;.;.;.;.;B;.;.
Vest4		0.14, 0.16, 0.23, 0.27, 0.22, 0.26, 0.26, 0.28
MutPred		0.24		.;Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);Gain of glycosylation at P12 (P = 0.0109);
MVP		0.72
MPC		1.8
ClinPred		0.28	T
GERP RS		5.3
PromoterAI		-0.051	Neutral
Varity_R		0.059
gMVP		0.35
Mutation Taster		=91/9	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: chr1-181452914;