rs2280866

Variant names:

• chr1-181737416-G-A
• rs2280866
• NM_001205293.3:c.3423-109G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-181737416-G-A
• chr1-181737416-G-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.3423-109G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,317,528 control chromosomes in the GnomAD database, including 114,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10880 hom., cov: 33)
  • Exomes 𝑓: 0.42 (104066 hom.)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24
• Publications: 1 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=-0.61).
• BP6: Variant 1-181737416-G-A is Benign according to our data. Variant chr1-181737416-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.3423-109G>A		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.3423-109G>A		intron_variant	Intron 22 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.3366-109G>A		intron_variant	Intron 21 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.3423-109G>A		intron_variant	Intron 22 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.3366-109G>A		intron_variant	Intron 21 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56012 AN: 151946 Hom.: 10861 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.352

GnomAD4 exome AF: 0.417 AC: 486471 AN: 1165466 Hom.: 104066 AF XY: 0.414 AC XY: 238337 AN XY: 576024

African (AFR) AF: 0.270 AC: 7259 AN: 26930

American (AMR) AF: 0.252 AC: 6624 AN: 26290

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 7841 AN: 18966

East Asian (EAS) AF: 0.277 AC: 9948 AN: 35958

South Asian (SAS) AF: 0.267 AC: 17132 AN: 64230

European-Finnish (FIN) AF: 0.405 AC: 16696 AN: 41274

Middle Eastern (MID) AF: 0.337 AC: 1267 AN: 3760

European-Non Finnish (NFE) AF: 0.446 AC: 400383 AN: 898484

Other (OTH) AF: 0.390 AC: 19321 AN: 49574

GnomAD4 genome AF: 0.369 AC: 56070 AN: 152062 Hom.: 10880 Cov.: 33 AF XY: 0.364 AC XY: 27047 AN XY: 74324

African (AFR) AF: 0.279 AC: 11571 AN: 41482

American (AMR) AF: 0.316 AC: 4828 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1487 AN: 3472

East Asian (EAS) AF: 0.250 AC: 1287 AN: 5148

South Asian (SAS) AF: 0.255 AC: 1233 AN: 4830

European-Finnish (FIN) AF: 0.397 AC: 4199 AN: 10582

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30223 AN: 67942

Other (OTH) AF: 0.357 AC: 753 AN: 2110

Alfa AF: 0.387 Hom.: 2316

Bravo AF: 0.357

Asia WGS AF: 0.264 AC: 922 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 11, 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	-0.61
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		1.2
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: rs2280866; hg19: chr1-181706552; COSMIC: COSV62385094;