NM_001205293.3:c.769+428G>A

Variant names:

• chr1-181579652-G-A
• rs3856090
• NM_001205293.3:c.769+428G>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.769+428G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 151,170 control chromosomes in the GnomAD database, including 9,164 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 0.34 (9164 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 3 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=-1.03).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.769+428G>A		intron_variant	Intron 5 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.769+428G>A		intron_variant	Intron 5 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.769+428G>A		intron_variant	Intron 5 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.769+428G>A		intron_variant	Intron 5 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.769+428G>A		intron_variant	Intron 5 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.1204+428G>A		intron_variant	Intron 7 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51535 AN: 151066 Hom.: 9160 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.341 AC: 51539 AN: 151170 Hom.: 9164 Cov.: 32 AF XY: 0.341 AC XY: 25160 AN XY: 73826

African (AFR) AF: 0.239 AC: 9868 AN: 41218

American (AMR) AF: 0.454 AC: 6892 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1368 AN: 3456

East Asian (EAS) AF: 0.312 AC: 1605 AN: 5152

South Asian (SAS) AF: 0.460 AC: 2203 AN: 4786

European-Finnish (FIN) AF: 0.339 AC: 3507 AN: 10332

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24768 AN: 67734

Other (OTH) AF: 0.391 AC: 820 AN: 2098

Alfa AF: 0.339 Hom.: 4601

Bravo AF: 0.346

Asia WGS AF: 0.413 AC: 1430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.19
PhyloP100		-1.4
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: rs3856090; hg19: chr1-181548788; COSMIC: COSV107431191;