NM_001205293.3:c.4605+995G>A

Variant names:

• chr1-181759863-G-A
• rs4652679
• NM_001205293.3:c.4605+995G>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.4605+995G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,118 control chromosomes in the GnomAD database, including 5,083 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 0.26 (5083 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.807
• Publications: 6 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.4605+995G>A		intron_variant	Intron 32 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.4605+995G>A		intron_variant	Intron 32 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.4548+995G>A		intron_variant	Intron 31 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.4605+995G>A		intron_variant	Intron 32 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.4548+995G>A		intron_variant	Intron 31 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39036 AN: 152000 Hom.: 5077 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.275

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

GnomAD4 genome AF: 0.257 AC: 39057 AN: 152118 Hom.: 5083 Cov.: 32 AF XY: 0.256 AC XY: 19038 AN XY: 74362

African (AFR) AF: 0.275 AC: 11407 AN: 41494

American (AMR) AF: 0.285 AC: 4361 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3468

East Asian (EAS) AF: 0.0640 AC: 332 AN: 5186

South Asian (SAS) AF: 0.337 AC: 1622 AN: 4810

European-Finnish (FIN) AF: 0.241 AC: 2543 AN: 10572

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17260 AN: 67988

Other (OTH) AF: 0.273 AC: 577 AN: 2110

Alfa AF: 0.259 Hom.: 830

Bravo AF: 0.258

Asia WGS AF: 0.191 AC: 662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.62
DANN	Benign	0.44
PhyloP100		-0.81
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: rs4652679; hg19: chr1-181728999; COSMIC: COSV62400214;