NM_001205293.3:c.5863G>A

Variant names:

• chr1-181790521-G-A
• rs704326
• NM_001205293.3:c.5863G>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.5863G>A​(p.Ala1955Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,608,712 control chromosomes in the GnomAD database, including 152,777 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1955P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.36 (11150 hom., cov: 31)
  • Exomes 𝑓: 0.43 (141627 hom.)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.366
• Publications: 41 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 (MetaRNN=1.3509393E-4).
• BP6: Variant 1-181790521-G-A is Benign according to our data. Variant chr1-181790521-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.5863G>A	p.Ala1955Thr	missense	Exon 44 of 48	NP_001192222.1
	CACNA1E	NM_000721.4		c.5863G>A	p.Ala1955Thr	missense	Exon 44 of 47	NP_000712.2
	CACNA1E	NM_001205294.2		c.5806G>A	p.Ala1936Thr	missense	Exon 43 of 46	NP_001192223.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.5863G>A	p.Ala1955Thr	missense	Exon 44 of 48	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.5806G>A	p.Ala1936Thr	missense	Exon 43 of 47	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.5863G>A	p.Ala1955Thr	missense	Exon 44 of 47	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54185 AN: 151838 Hom.: 11138 Cov.: 31

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.388 AC: 96763 AN: 249132 AF XY: 0.389

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.433 AC: 630471 AN: 1456756 Hom.: 141627 Cov.: 32 AF XY: 0.428 AC XY: 310372 AN XY: 725032

African (AFR) AF: 0.139 AC: 4649 AN: 33420

American (AMR) AF: 0.336 AC: 15034 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 12992 AN: 26100

East Asian (EAS) AF: 0.420 AC: 16651 AN: 39674

South Asian (SAS) AF: 0.226 AC: 19455 AN: 86158

European-Finnish (FIN) AF: 0.448 AC: 23910 AN: 53386

Middle Eastern (MID) AF: 0.333 AC: 1920 AN: 5758

European-Non Finnish (NFE) AF: 0.462 AC: 511202 AN: 1107306

Other (OTH) AF: 0.409 AC: 24658 AN: 60240

GnomAD4 genome AF: 0.357 AC: 54219 AN: 151956 Hom.: 11150 Cov.: 31 AF XY: 0.354 AC XY: 26273 AN XY: 74272

African (AFR) AF: 0.154 AC: 6387 AN: 41464

American (AMR) AF: 0.360 AC: 5499 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1767 AN: 3466

East Asian (EAS) AF: 0.408 AC: 2107 AN: 5160

South Asian (SAS) AF: 0.218 AC: 1050 AN: 4806

European-Finnish (FIN) AF: 0.441 AC: 4647 AN: 10536

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31535 AN: 67928

Other (OTH) AF: 0.356 AC: 750 AN: 2108

Alfa AF: 0.431 Hom.: 71928

Bravo AF: 0.342

TwinsUK AF: 0.456 AC: 1690

ALSPAC AF: 0.455 AC: 1752

ESP6500AA AF: 0.155 AC: 591

ESP6500EA AF: 0.455 AC: 3736

ExAC AF: 0.386 AC: 46587

Asia WGS AF: 0.286 AC: 997 AN: 3478

EpiCase AF: 0.453

EpiControl AF: 0.458

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy, 69 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.9
DANN	Benign	0.67
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.37
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.25
Sift	Benign	0.68	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.050
MPC		0.25
ClinPred		0.00030	T
GERP RS		-1.5
Varity_R		0.025
gMVP		0.31
Mutation Taster		=99/1	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: rs704326; hg19: chr1-181759657; COSMIC: COSV62386678;