chr1-181580411-T-G

Variant names:

• chr1-181580411-T-G
• rs10494540
• NM_001205293.3:c.770-184T>G

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.770-184T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 151,956 control chromosomes in the GnomAD database, including 17,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.48 (17993 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.874
• Publications: 6 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 (BayesDel_noAF=-0.83).
• BP6: Variant 1-181580411-T-G is Benign according to our data. Variant chr1-181580411-T-G is described in ClinVar as Benign. ClinVar VariationId is 1236032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.770-184T>G		intron	N/A	NP_001192222.1
	CACNA1E	NM_000721.4		c.770-184T>G		intron	N/A	NP_000712.2
	CACNA1E	NM_001205294.2		c.770-184T>G		intron	N/A	NP_001192223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.770-184T>G		intron	N/A	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.770-184T>G		intron	N/A	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.770-184T>G		intron	N/A	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72832 AN: 151838 Hom.: 17966 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.443

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.480 AC: 72909 AN: 151956 Hom.: 17993 Cov.: 32 AF XY: 0.485 AC XY: 35988 AN XY: 74274

African (AFR) AF: 0.415 AC: 17173 AN: 41420

American (AMR) AF: 0.427 AC: 6529 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1836 AN: 3468

East Asian (EAS) AF: 0.664 AC: 3417 AN: 5146

South Asian (SAS) AF: 0.379 AC: 1823 AN: 4816

European-Finnish (FIN) AF: 0.548 AC: 5787 AN: 10564

Middle Eastern (MID) AF: 0.431 AC: 125 AN: 290

European-Non Finnish (NFE) AF: 0.512 AC: 34817 AN: 67952

Other (OTH) AF: 0.448 AC: 942 AN: 2102

Alfa AF: 0.494 Hom.: 29648

Bravo AF: 0.468

Asia WGS AF: 0.476 AC: 1657 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 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.68
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10494540; hg19: chr1-181549547;