rs2280868

Variant names:

• chr1-181772675-C-A
• rs2280868
• NM_001205293.3:c.5139+444C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001205293.3(CACNA1E):​c.5139+444C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 151,922 control chromosomes in the GnomAD database, including 916 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 0.10 (916 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.441
• 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: Illumina, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.5139+444C>A		intron	N/A	NP_001192222.1	Q15878-1
	CACNA1E	NM_000721.4		c.5139+444C>A		intron	N/A	NP_000712.2	Q15878-3
	CACNA1E	NM_001205294.2		c.5082+444C>A		intron	N/A	NP_001192223.1	Q15878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.5139+444C>A		intron	N/A	ENSP00000356545.2	Q15878-1
	CACNA1E	ENST00000360108.7	TSL:5	c.5082+444C>A		intron	N/A	ENSP00000353222.3	F8W9Z1
	CACNA1E	ENST00000367570.6	TSL:1	c.5139+444C>A		intron	N/A	ENSP00000356542.1	Q15878-3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15860 AN: 151804 Hom.: 915 Cov.: 32

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.0821

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0979

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.104 AC: 15857 AN: 151922 Hom.: 916 Cov.: 32 AF XY: 0.106 AC XY: 7837 AN XY: 74226

African (AFR) AF: 0.0568 AC: 2351 AN: 41426

American (AMR) AF: 0.0820 AC: 1252 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3470

East Asian (EAS) AF: 0.192 AC: 989 AN: 5158

South Asian (SAS) AF: 0.0988 AC: 475 AN: 4806

European-Finnish (FIN) AF: 0.136 AC: 1427 AN: 10524

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8337 AN: 67950

Other (OTH) AF: 0.110 AC: 231 AN: 2108

Alfa AF: 0.114 Hom.: 2223

Bravo AF: 0.0988

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.71
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2280868; hg19: chr1-181741811;