rs17494681

Variant names:

• chr1-181511047-C-T
• rs17494681
• NM_001205293.3:c.373-324C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001205293.3(CACNA1E):​c.373-324C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,244 control chromosomes in the GnomAD database, including 1,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1729 hom., cov: 33)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.441
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-181511047-C-T is Benign according to our data. Variant chr1-181511047-C-T is described in ClinVar as Benign. ClinVar VariationId is 1296142.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.373-324C>T		intron_variant	Intron 2 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.373-324C>T		intron_variant	Intron 2 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.373-324C>T		intron_variant	Intron 2 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.373-324C>T		intron_variant	Intron 2 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.373-324C>T		intron_variant	Intron 2 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.808-324C>T		intron_variant	Intron 4 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21629 AN: 152126 Hom.: 1730 Cov.: 33

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.169

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

GnomAD4 genome AF: 0.142 AC: 21624 AN: 152244 Hom.: 1729 Cov.: 33 AF XY: 0.142 AC XY: 10534 AN XY: 74428

African (AFR) AF: 0.0809 AC: 3361 AN: 41558

American (AMR) AF: 0.130 AC: 1991 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 846 AN: 3472

East Asian (EAS) AF: 0.0697 AC: 361 AN: 5176

South Asian (SAS) AF: 0.110 AC: 530 AN: 4826

European-Finnish (FIN) AF: 0.168 AC: 1778 AN: 10600

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12166 AN: 67998

Other (OTH) AF: 0.167 AC: 352 AN: 2112

Alfa AF: 0.171 Hom.: 3638

Bravo AF: 0.139

Asia WGS AF: 0.0970 AC: 338 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 22, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.59
DANN	Benign	0.71
PhyloP100		-0.44
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: rs17494681; hg19: chr1-181480183;