NM_001205293.3:c.*216T>C

Variant names:

• chr1-181799050-T-C
• rs2280869
• NM_001205293.3:c.*216T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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 -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 VariationId 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 rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.*216T>C		3_prime_UTR_variant	Exon 48 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.*216T>C		3_prime_UTR_variant	Exon 48 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000367570.6	c.*216T>C		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.*216T>C		3_prime_UTR_variant	Exon 46 of 46	1		ENSP00000481619.1
CACNA1E	ENST00000360108.7	c.*216T>C		downstream_gene_variant		5		ENSP00000353222.3

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

African (AFR) AF: 0.0751 AC: 664 AN: 8838

American (AMR) AF: 0.159 AC: 1659 AN: 10410

Ashkenazi Jewish (ASJ) AF: 0.0659 AC: 672 AN: 10196

East Asian (EAS) AF: 0.304 AC: 7321 AN: 24086

South Asian (SAS) AF: 0.115 AC: 1324 AN: 11476

European-Finnish (FIN) AF: 0.0565 AC: 1269 AN: 22464

Middle Eastern (MID) AF: 0.0414 AC: 61 AN: 1472

European-Non Finnish (NFE) AF: 0.0554 AC: 10481 AN: 189076

Other (OTH) AF: 0.0794 AC: 1481 AN: 18658

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

African (AFR) AF: 0.0748 AC: 3111 AN: 41568

American (AMR) AF: 0.143 AC: 2191 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 205 AN: 3472

East Asian (EAS) AF: 0.288 AC: 1483 AN: 5146

South Asian (SAS) AF: 0.114 AC: 552 AN: 4824

European-Finnish (FIN) AF: 0.0653 AC: 693 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0538 AC: 3659 AN: 68032

Other (OTH) AF: 0.0705 AC: 149 AN: 2114

Alfa AF: 0.0619 Hom.: 419

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		0.34
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: rs2280869; hg19: chr1-181768186;