rs704326

chr1-181790521-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. A1955A) has been classified as Likely benign.

• 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:3
• Conservation: PhyloP100: 0.366

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1E
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1E	NM_001205293.3	c.5863G>A	p.Ala1955Thr	missense_variant	44/48	ENST00000367573.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1E	ENST00000367573.7	c.5863G>A	p.Ala1955Thr	missense_variant	44/48	1	NM_001205293.3	A2
CACNA1E	ENST00000367570.6	c.5863G>A	p.Ala1955Thr	missense_variant	44/47	1		P4
CACNA1E	ENST00000621791.4	c.5806G>A	p.Ala1936Thr	missense_variant	43/46	1		A2
CACNA1E	ENST00000360108.7	c.5806G>A	p.Ala1936Thr	missense_variant	43/47	5		A2

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

GnomAD3 exomes AF: 0.388 AC: 96763 AN: 249132 Hom.: 20201 AF XY: 0.389 AC XY: 52582 AN XY: 135166

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 SAS exome AF: 0.221

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

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.420

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.462

Gnomad4 OTH exome AF: 0.409

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

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.356

Alfa AF: 0.440 Hom.: 39844

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -

Developmental and epileptic encephalopathy, 69 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.042	N
MetaRNN	Benign	0.00014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.;L;.;L;L;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.38	N;.;N;N;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.68	T;.;T;T;.;.;.;.
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;B;.;B
Vest4		0.050
MPC		0.25
ClinPred		0.00030	T
GERP RS		-1.5
Varity_R		0.025
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs704326; hg19: chr1-181759657; COSMIC: COSV62386678;