rs494288

Variant names:

• chr1-181496218-T-C
• rs494288
• NM_001205293.3:c.266+12208T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001205293.3(CACNA1E):​c.266+12208T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 152,102 control chromosomes in the GnomAD database, including 10,389 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10389 hom., cov: 33)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.266+12208T>C		intron_variant	Intron 1 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.266+12208T>C		intron_variant	Intron 1 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.266+12208T>C		intron_variant	Intron 1 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.266+12208T>C		intron_variant	Intron 1 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.266+12208T>C		intron_variant	Intron 1 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.701+12208T>C		intron_variant	Intron 3 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53924 AN: 151984 Hom.: 10357 Cov.: 33

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.356

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.355 AC: 54017 AN: 152102 Hom.: 10389 Cov.: 33 AF XY: 0.351 AC XY: 26075 AN XY: 74370

African (AFR) AF: 0.497 AC: 20600 AN: 41460

American (AMR) AF: 0.390 AC: 5962 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1109 AN: 3468

East Asian (EAS) AF: 0.307 AC: 1586 AN: 5168

South Asian (SAS) AF: 0.305 AC: 1469 AN: 4820

European-Finnish (FIN) AF: 0.243 AC: 2579 AN: 10610

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19682 AN: 67982

Other (OTH) AF: 0.355 AC: 749 AN: 2112

Alfa AF: 0.330 Hom.: 4858

Bravo AF: 0.372

Asia WGS AF: 0.318 AC: 1105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.78
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs494288; hg19: chr1-181465354;