1-181508389-C-T

Variant names:

• chr1-181508389-C-T
• rs558994
• NM_001205293.3:c.267-2088C>T

Variant summary

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

The NM_001205293.3(CACNA1E):​c.267-2088C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,072 control chromosomes in the GnomAD database, including 8,238 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 0.32 (8238 hom., cov: 33)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 7 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

ENSG00000302070 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.267-2088C>T		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.267-2088C>T		intron_variant	Intron 1 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.267-2088C>T		intron_variant	Intron 1 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.267-2088C>T		intron_variant	Intron 1 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.267-2088C>T		intron_variant	Intron 1 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.702-2088C>T		intron_variant	Intron 3 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48723 AN: 151954 Hom.: 8227 Cov.: 33

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.335

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

GnomAD4 genome AF: 0.321 AC: 48777 AN: 152072 Hom.: 8238 Cov.: 33 AF XY: 0.314 AC XY: 23306 AN XY: 74338

African (AFR) AF: 0.426 AC: 17665 AN: 41446

American (AMR) AF: 0.268 AC: 4099 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1605 AN: 3470

East Asian (EAS) AF: 0.345 AC: 1779 AN: 5158

South Asian (SAS) AF: 0.161 AC: 775 AN: 4820

European-Finnish (FIN) AF: 0.242 AC: 2559 AN: 10578

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.283 AC: 19270 AN: 67988

Other (OTH) AF: 0.331 AC: 698 AN: 2110

Alfa AF: 0.301 Hom.: 21705

Bravo AF: 0.332

Asia WGS AF: 0.250 AC: 871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.40
DANN	Benign	0.54
PhyloP100		-0.16
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: rs558994; hg19: chr1-181477525;