1-181761090-A-G

Variant names:

• chr1-181761090-A-G
• rs697260
• NM_001205293.3:c.4606-1484A>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.4606-1484A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 152,152 control chromosomes in the GnomAD database, including 54,407 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 0.84 (54407 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.142
• Publications: 6 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.871 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.4606-1484A>G		intron	N/A	NP_001192222.1
	CACNA1E	NM_000721.4		c.4606-1484A>G		intron	N/A	NP_000712.2
	CACNA1E	NM_001205294.2		c.4549-1484A>G		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.4606-1484A>G		intron	N/A	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.4549-1484A>G		intron	N/A	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.4606-1484A>G		intron	N/A	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128362 AN: 152034 Hom.: 54354 Cov.: 32

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.894

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.870

Gnomad OTH AF: 0.837

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

GnomAD4 genome AF: 0.844 AC: 128472 AN: 152152 Hom.: 54407 Cov.: 32 AF XY: 0.846 AC XY: 62913 AN XY: 74368

African (AFR) AF: 0.781 AC: 32431 AN: 41504

American (AMR) AF: 0.876 AC: 13384 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2915 AN: 3470

East Asian (EAS) AF: 0.815 AC: 4224 AN: 5182

South Asian (SAS) AF: 0.894 AC: 4295 AN: 4806

European-Finnish (FIN) AF: 0.872 AC: 9245 AN: 10604

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.870 AC: 59125 AN: 67986

Other (OTH) AF: 0.839 AC: 1772 AN: 2112

Alfa AF: 0.862 Hom.: 32546

Bravo AF: 0.841

Asia WGS AF: 0.822 AC: 2861 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.3
DANN	Benign	0.52
PhyloP100		0.14
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: rs697260; hg19: chr1-181730226;