rs7540850

Positions:

• chr1-181717080-T-C
• chr1-181717080-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001205293.3(CACNA1E):​c.1316-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,610,998 control chromosomes in the GnomAD database, including 406,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (30270 hom., cov: 33)
  • Exomes 𝑓: 0.71 (376464 hom.)
• Consequence: CACNA1E NM_001205293.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.190

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-181717080-T-C is Benign according to our data. Variant chr1-181717080-T-C is described in ClinVar as [Benign]. Clinvar id is 1192683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.1316-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.1316-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001205293.3	ENSP00000356545	A2
CACNA1E	ENST00000367570.6	c.1316-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000356542	P4
CACNA1E	ENST00000621791.4	c.1316-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000481619	A2
CACNA1E	ENST00000360108.7	c.1316-13T>C		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000353222	A2

Frequencies

GnomAD3 genomes AF: 0.599 AC: 91163 AN: 152078 Hom.: 30249 Cov.: 33

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.599

GnomAD3 exomes AF: 0.681 AC: 169553 AN: 248938 Hom.: 59333 AF XY: 0.688 AC XY: 92939 AN XY: 135050

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.754

Gnomad SAS exome AF: 0.653

Gnomad FIN exome AF: 0.757

Gnomad NFE exome AF: 0.726

Gnomad OTH exome AF: 0.699

GnomAD4 exome AF: 0.714 AC: 1041334 AN: 1458802 Hom.: 376464 Cov.: 33 AF XY: 0.713 AC XY: 517811 AN XY: 725946

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.651

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.652

Gnomad4 FIN exome AF: 0.756

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.599 AC: 91215 AN: 152196 Hom.: 30270 Cov.: 33 AF XY: 0.605 AC XY: 45020 AN XY: 74424

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.768

Gnomad4 SAS AF: 0.655

Gnomad4 FIN AF: 0.760

Gnomad4 NFE AF: 0.727

Gnomad4 OTH AF: 0.603

Alfa AF: 0.689 Hom.: 38631

Bravo AF: 0.577

Asia WGS AF: 0.667 AC: 2321 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2021	- -

Developmental and epileptic encephalopathy, 69 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.5
DANN	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7540850; hg19: chr1-181686216; COSMIC: COSV62386641; COSMIC: COSV62386641;