rs3845445

Variant names:

• chr1-181737065-A-G
• rs3845445
• NM_001205293.3:c.3423-460A>G

Variant summary

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

The NM_001205293.3(CACNA1E):​c.3423-460A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,194 control chromosomes in the GnomAD database, including 2,216 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 0.17 (2216 hom., cov: 33)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.3423-460A>G		intron_variant	Intron 22 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.3423-460A>G		intron_variant	Intron 22 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.3366-460A>G		intron_variant	Intron 21 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.3423-460A>G		intron_variant	Intron 22 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.3366-460A>G		intron_variant	Intron 21 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25365 AN: 152076 Hom.: 2215 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.167 AC: 25355 AN: 152194 Hom.: 2216 Cov.: 33 AF XY: 0.167 AC XY: 12442 AN XY: 74416

African (AFR) AF: 0.228 AC: 9465 AN: 41494

American (AMR) AF: 0.146 AC: 2227 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3472

East Asian (EAS) AF: 0.0458 AC: 238 AN: 5192

South Asian (SAS) AF: 0.252 AC: 1213 AN: 4822

European-Finnish (FIN) AF: 0.130 AC: 1375 AN: 10600

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9696 AN: 68000

Other (OTH) AF: 0.170 AC: 360 AN: 2116

Alfa AF: 0.156 Hom.: 1044

Bravo AF: 0.168

Asia WGS AF: 0.132 AC: 458 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.77
PhyloP100		-1.1
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: rs3845445; hg19: chr1-181706201;