rs199943

Variant names:

• chr1-181629264-C-A
• rs199943
• NM_001205293.3:c.952-22074C>A

Variant summary

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

The NM_001205293.3(CACNA1E):​c.952-22074C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 150,594 control chromosomes in the GnomAD database, including 45,676 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 0.77 (45676 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 2 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 (EAS) allele frequency at 95% confidence interval = 0.919 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.952-22074C>A		intron	N/A	NP_001192222.1
	CACNA1E	NM_000721.4		c.952-22074C>A		intron	N/A	NP_000712.2
	CACNA1E	NM_001205294.2		c.952-22074C>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.952-22074C>A		intron	N/A	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.952-22074C>A		intron	N/A	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.952-22074C>A		intron	N/A	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 116485 AN: 150486 Hom.: 45639 Cov.: 32

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.773

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

GnomAD4 genome AF: 0.774 AC: 116568 AN: 150594 Hom.: 45676 Cov.: 32 AF XY: 0.776 AC XY: 57160 AN XY: 73624

African (AFR) AF: 0.626 AC: 25026 AN: 39996

American (AMR) AF: 0.791 AC: 12066 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 2957 AN: 3472

East Asian (EAS) AF: 0.941 AC: 4867 AN: 5174

South Asian (SAS) AF: 0.647 AC: 3117 AN: 4816

European-Finnish (FIN) AF: 0.878 AC: 9307 AN: 10596

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56733 AN: 67988

Other (OTH) AF: 0.774 AC: 1629 AN: 2104

Alfa AF: 0.810 Hom.: 29253

Bravo AF: 0.759

Asia WGS AF: 0.778 AC: 2695 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.78
DANN	Benign	0.61
PhyloP100		-0.078
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: rs199943; hg19: chr1-181598400;