rs2280869

Positions:

• chr1-181799050-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001205293.3(CACNA1E):​c.*216T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 448,958 control chromosomes in the GnomAD database, including 2,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (711 hom., cov: 33)
  • Exomes 𝑓: 0.084 (1781 hom.)
• Consequence: CACNA1E NM_001205293.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.345

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-181799050-T-C is Benign according to our data. Variant chr1-181799050-T-C is described in ClinVar as [Benign]. Clinvar id is 1228100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.*216T>C		3_prime_UTR_variant	48/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.*216T>C		3_prime_UTR_variant	48/48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000367570.6	c.*216T>C		3_prime_UTR_variant	47/47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.*216T>C		3_prime_UTR_variant	46/46	1		ENSP00000481619.1
CACNA1E	ENST00000700190.1	c.498+2192T>C		intron_variant				ENSP00000514852.1

Frequencies

GnomAD3 genomes AF: 0.0802 AC: 12203 AN: 152164 Hom.: 706 Cov.: 33

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0653

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0717

GnomAD4 exome AF: 0.0840 AC: 24932 AN: 296676 Hom.: 1781 Cov.: 4 AF XY: 0.0844 AC XY: 12737 AN XY: 150888

Gnomad4 AFR exome AF: 0.0751

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.0659

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.0565

Gnomad4 NFE exome AF: 0.0554

Gnomad4 OTH exome AF: 0.0794

GnomAD4 genome AF: 0.0801 AC: 12203 AN: 152282 Hom.: 711 Cov.: 33 AF XY: 0.0851 AC XY: 6339 AN XY: 74454

Gnomad4 AFR AF: 0.0748

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.0590

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0653

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0615 Hom.: 337

Bravo AF: 0.0868

Asia WGS AF: 0.179 AC: 624 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.75

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: rs2280869; hg19: chr1-181768186;