rs12239392

Variant names:

• chr1-181583934-G-A
• rs12239392
• NM_001205293.3:c.951+3158G>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.951+3158G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 151,968 control chromosomes in the GnomAD database, including 1,379 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 0.12 (1379 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.639
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.951+3158G>A		intron_variant	Intron 6 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.951+3158G>A		intron_variant	Intron 6 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.951+3158G>A		intron_variant	Intron 6 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.951+3158G>A		intron_variant	Intron 6 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.951+3158G>A		intron_variant	Intron 6 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.1386+3158G>A		intron_variant	Intron 8 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18604 AN: 151850 Hom.: 1381 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.122 AC: 18600 AN: 151968 Hom.: 1379 Cov.: 32 AF XY: 0.122 AC XY: 9068 AN XY: 74270

African (AFR) AF: 0.197 AC: 8174 AN: 41412

American (AMR) AF: 0.138 AC: 2113 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5174

South Asian (SAS) AF: 0.220 AC: 1053 AN: 4794

European-Finnish (FIN) AF: 0.0356 AC: 375 AN: 10544

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0855 AC: 5810 AN: 67982

Other (OTH) AF: 0.126 AC: 267 AN: 2116

Alfa AF: 0.102 Hom.: 1640

Bravo AF: 0.132

Asia WGS AF: 0.134 AC: 465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.91
PhyloP100		-0.64
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: rs12239392; hg19: chr1-181553070;