1-181666818-A-G

Variant names:

• chr1-181666818-A-G
• rs199916
• NM_001205293.3:c.1055+15377A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001205293.3(CACNA1E):​c.1055+15377A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 152,016 control chromosomes in the GnomAD database, including 59,916 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (59916 hom., cov: 31)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.304
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 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.1055+15377A>G		intron	N/A	NP_001192222.1
	CACNA1E	NM_000721.4		c.1055+15377A>G		intron	N/A	NP_000712.2
	CACNA1E	NM_001205294.2		c.1055+15377A>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.1055+15377A>G		intron	N/A	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.1055+15377A>G		intron	N/A	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.1055+15377A>G		intron	N/A	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.886 AC: 134630 AN: 151898 Hom.: 59854 Cov.: 31

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.852

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

GnomAD4 genome AF: 0.886 AC: 134749 AN: 152016 Hom.: 59916 Cov.: 31 AF XY: 0.888 AC XY: 65971 AN XY: 74286

African (AFR) AF: 0.960 AC: 39866 AN: 41520

American (AMR) AF: 0.846 AC: 12917 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 2956 AN: 3466

East Asian (EAS) AF: 0.823 AC: 4258 AN: 5174

South Asian (SAS) AF: 0.905 AC: 4361 AN: 4820

European-Finnish (FIN) AF: 0.868 AC: 9165 AN: 10558

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58351 AN: 67892

Other (OTH) AF: 0.855 AC: 1803 AN: 2110

Alfa AF: 0.860 Hom.: 108922

Bravo AF: 0.884

Asia WGS AF: 0.858 AC: 2981 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.0
DANN	Benign	0.43
PhyloP100		-0.30
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: rs199916; hg19: chr1-181635954;