chr1-181758137-G-A

Variant names:

• chr1-181758137-G-A
• rs704329
• NM_001205293.3:c.4494+26G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001205293.3(CACNA1E):​c.4494+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,603,568 control chromosomes in the GnomAD database, including 156,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11469 hom., cov: 32)
  • Exomes 𝑓: 0.44 (145461 hom.)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.442
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-181758137-G-A is Benign according to our data. Variant chr1-181758137-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.4494+26G>A		intron_variant	Intron 31 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.4494+26G>A		intron_variant	Intron 31 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.4437+26G>A		intron_variant	Intron 30 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.4494+26G>A		intron_variant	Intron 31 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.4437+26G>A		intron_variant	Intron 30 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56239 AN: 151910 Hom.: 11455 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.408 AC: 99866 AN: 244522 AF XY: 0.417

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.399

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.444 AC: 644319 AN: 1451540 Hom.: 145461 Cov.: 31 AF XY: 0.444 AC XY: 320164 AN XY: 721164

African (AFR) AF: 0.177 AC: 5903 AN: 33286

American (AMR) AF: 0.319 AC: 14151 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10734 AN: 25878

East Asian (EAS) AF: 0.441 AC: 17433 AN: 39500

South Asian (SAS) AF: 0.415 AC: 35478 AN: 85560

European-Finnish (FIN) AF: 0.462 AC: 24572 AN: 53186

Middle Eastern (MID) AF: 0.357 AC: 1797 AN: 5030

European-Non Finnish (NFE) AF: 0.461 AC: 509451 AN: 1104814

Other (OTH) AF: 0.414 AC: 24800 AN: 59904

GnomAD4 genome AF: 0.370 AC: 56277 AN: 152028 Hom.: 11469 Cov.: 32 AF XY: 0.372 AC XY: 27662 AN XY: 74314

African (AFR) AF: 0.190 AC: 7886 AN: 41488

American (AMR) AF: 0.348 AC: 5317 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1481 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2179 AN: 5158

South Asian (SAS) AF: 0.428 AC: 2062 AN: 4818

European-Finnish (FIN) AF: 0.464 AC: 4891 AN: 10546

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.459 AC: 31225 AN: 67962

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

Alfa AF: 0.422 Hom.: 29452

Bravo AF: 0.350

Asia WGS AF: 0.415 AC: 1441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.70
DANN	Benign	0.45
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: rs704329; hg19: chr1-181727273; COSMIC: COSV62392227;