rs553042

Variant names:

• chr1-181487564-T-C
• rs553042
• NM_001205293.3:c.266+3554T>C

Variant summary

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

The NM_001205293.3(CACNA1E):​c.266+3554T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,154 control chromosomes in the GnomAD database, including 7,044 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 0.30 (7044 hom., cov: 33)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690
• 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=-0.59).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.266+3554T>C		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.266+3554T>C		intron_variant	Intron 1 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.266+3554T>C		intron_variant	Intron 1 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.266+3554T>C		intron_variant	Intron 1 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.266+3554T>C		intron_variant	Intron 1 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.701+3554T>C		intron_variant	Intron 3 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45966 AN: 152036 Hom.: 7039 Cov.: 33

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.317

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

GnomAD4 genome AF: 0.302 AC: 46021 AN: 152154 Hom.: 7044 Cov.: 33 AF XY: 0.299 AC XY: 22268 AN XY: 74386

African (AFR) AF: 0.319 AC: 13246 AN: 41496

American (AMR) AF: 0.364 AC: 5564 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1101 AN: 3470

East Asian (EAS) AF: 0.302 AC: 1565 AN: 5182

South Asian (SAS) AF: 0.303 AC: 1466 AN: 4832

European-Finnish (FIN) AF: 0.243 AC: 2569 AN: 10590

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19568 AN: 67984

Other (OTH) AF: 0.316 AC: 668 AN: 2112

Alfa AF: 0.296 Hom.: 25959

Bravo AF: 0.312

Asia WGS AF: 0.302 AC: 1048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		0.069
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: rs553042; hg19: chr1-181456700;