1-181545790-T-A

Variant names:

• chr1-181545790-T-A
• rs2184945
• NM_001205293.3:c.513-31976T>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.513-31976T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 152,070 control chromosomes in the GnomAD database, including 16,969 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 0.45 (16969 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.513-31976T>A		intron_variant	Intron 3 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.513-31976T>A		intron_variant	Intron 3 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.513-31976T>A		intron_variant	Intron 3 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.513-31976T>A		intron_variant	Intron 3 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.513-31976T>A		intron_variant	Intron 3 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.948-31976T>A		intron_variant	Intron 5 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68335 AN: 151952 Hom.: 16965 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.479

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

GnomAD4 genome AF: 0.449 AC: 68341 AN: 152070 Hom.: 16969 Cov.: 32 AF XY: 0.453 AC XY: 33631 AN XY: 74322

African (AFR) AF: 0.237 AC: 9844 AN: 41512

American (AMR) AF: 0.460 AC: 7029 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1897 AN: 3464

East Asian (EAS) AF: 0.500 AC: 2578 AN: 5152

South Asian (SAS) AF: 0.464 AC: 2236 AN: 4822

European-Finnish (FIN) AF: 0.562 AC: 5936 AN: 10570

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37008 AN: 67952

Other (OTH) AF: 0.482 AC: 1016 AN: 2108

Alfa AF: 0.497 Hom.: 2471

Bravo AF: 0.434

Asia WGS AF: 0.474 AC: 1649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.35
PhyloP100		0.063
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: rs2184945; hg19: chr1-181514926;