rs12138634

Variant names:

• chr1-181581647-T-G
• rs12138634
• NM_001205293.3:c.951+871T>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.951+871T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 151,978 control chromosomes in the GnomAD database, including 15,940 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 0.44 (15940 hom., cov: 31)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.951+871T>G		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+871T>G		intron_variant	Intron 6 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.951+871T>G		intron_variant	Intron 6 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.951+871T>G		intron_variant	Intron 6 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.951+871T>G		intron_variant	Intron 6 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.1386+871T>G		intron_variant	Intron 8 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67166 AN: 151858 Hom.: 15912 Cov.: 31

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.411

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

GnomAD4 genome AF: 0.442 AC: 67243 AN: 151978 Hom.: 15940 Cov.: 31 AF XY: 0.448 AC XY: 33293 AN XY: 74280

African (AFR) AF: 0.287 AC: 11881 AN: 41434

American (AMR) AF: 0.410 AC: 6262 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1842 AN: 3468

East Asian (EAS) AF: 0.665 AC: 3431 AN: 5162

South Asian (SAS) AF: 0.377 AC: 1814 AN: 4810

European-Finnish (FIN) AF: 0.548 AC: 5781 AN: 10556

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34772 AN: 67962

Other (OTH) AF: 0.417 AC: 879 AN: 2108

Alfa AF: 0.474 Hom.: 6422

Bravo AF: 0.426

Asia WGS AF: 0.469 AC: 1634 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	1.9
DANN	Benign	0.68
PhyloP100		-0.073
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: rs12138634; hg19: chr1-181550783;