1-181676091-G-A

Variant names:

• chr1-181676091-G-A
• rs3753737
• NM_001205293.3:c.1055+24650G>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.1055+24650G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 151,742 control chromosomes in the GnomAD database, including 30,796 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 0.63 (30796 hom., cov: 29)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.1055+24650G>A		intron_variant	Intron 7 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.1055+24650G>A		intron_variant	Intron 7 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.1055+24650G>A		intron_variant	Intron 7 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.1055+24650G>A		intron_variant	Intron 7 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.1055+24650G>A		intron_variant	Intron 7 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.1490+24650G>A		intron_variant	Intron 9 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.626 AC: 94880 AN: 151624 Hom.: 30793 Cov.: 29

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.733

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.610

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

GnomAD4 genome AF: 0.625 AC: 94905 AN: 151742 Hom.: 30796 Cov.: 29 AF XY: 0.630 AC XY: 46767 AN XY: 74180

African (AFR) AF: 0.447 AC: 18484 AN: 41308

American (AMR) AF: 0.611 AC: 9326 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 2540 AN: 3466

East Asian (EAS) AF: 0.789 AC: 4051 AN: 5132

South Asian (SAS) AF: 0.654 AC: 3133 AN: 4794

European-Finnish (FIN) AF: 0.710 AC: 7473 AN: 10524

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47685 AN: 67934

Other (OTH) AF: 0.614 AC: 1299 AN: 2114

Alfa AF: 0.676 Hom.: 22194

Bravo AF: 0.609

Asia WGS AF: 0.651 AC: 2266 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.58
PhyloP100		-1.6
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: rs3753737; hg19: chr1-181645227;