rs12405860

Variant names:

• chr1-181505142-A-G
• rs12405860
• NM_001205293.3:c.267-5335A>G

Variant summary

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

The NM_001205293.3(CACNA1E):​c.267-5335A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 152,164 control chromosomes in the GnomAD database, including 612 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 0.075 (612 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.302
• Publications: 1 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.267-5335A>G		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.267-5335A>G		intron_variant	Intron 1 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.267-5335A>G		intron_variant	Intron 1 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.267-5335A>G		intron_variant	Intron 1 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.267-5335A>G		intron_variant	Intron 1 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.702-5335A>G		intron_variant	Intron 3 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.0747 AC: 11351 AN: 152046 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0782

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.0803

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0750

Gnomad OTH AF: 0.0817

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

GnomAD4 genome AF: 0.0746 AC: 11356 AN: 152164 Hom.: 612 Cov.: 32 AF XY: 0.0800 AC XY: 5952 AN XY: 74394

African (AFR) AF: 0.0295 AC: 1225 AN: 41536

American (AMR) AF: 0.116 AC: 1773 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0782 AC: 271 AN: 3466

East Asian (EAS) AF: 0.128 AC: 663 AN: 5166

South Asian (SAS) AF: 0.260 AC: 1252 AN: 4820

European-Finnish (FIN) AF: 0.0803 AC: 850 AN: 10584

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0750 AC: 5096 AN: 67984

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.0711 Hom.: 101

Bravo AF: 0.0725

Asia WGS AF: 0.171 AC: 591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.37
PhyloP100		-0.30
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: rs12405860; hg19: chr1-181474278;