rs2225875

Variant names:

• chr1-181537403-G-A
• rs2225875
• NM_001205293.3:c.512+25893G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-181537403-G-A
• chr1-181537403-G-C

Variant summary

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

The ENST00000367573.7(CACNA1E):​c.512+25893G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,940 control chromosomes in the GnomAD database, including 8,999 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 0.33 (8999 hom., cov: 31)
• Consequence: CACNA1E ENST00000367573.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367573.7. 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.512+25893G>A		intron	N/A	NP_001192222.1
	CACNA1E	NM_000721.4		c.512+25893G>A		intron	N/A	NP_000712.2
	CACNA1E	NM_001205294.2		c.512+25893G>A		intron	N/A	NP_001192223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.512+25893G>A		intron	N/A	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.512+25893G>A		intron	N/A	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.512+25893G>A		intron	N/A	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50620 AN: 151822 Hom.: 8983 Cov.: 31

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.334 AC: 50674 AN: 151940 Hom.: 8999 Cov.: 31 AF XY: 0.324 AC XY: 24095 AN XY: 74264

African (AFR) AF: 0.440 AC: 18228 AN: 41438

American (AMR) AF: 0.303 AC: 4615 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1126 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1121 AN: 5168

South Asian (SAS) AF: 0.143 AC: 691 AN: 4816

European-Finnish (FIN) AF: 0.275 AC: 2904 AN: 10550

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21068 AN: 67936

Other (OTH) AF: 0.308 AC: 649 AN: 2108

Alfa AF: 0.311 Hom.: 3966

Bravo AF: 0.342

Asia WGS AF: 0.207 AC: 721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.84
PhyloP100		0.11
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: rs2225875; hg19: chr1-181506539;