1-181746010-A-G

Variant names:

• chr1-181746010-A-G
• rs3753748
• NM_001205293.3:c.3720-4466A>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.3720-4466A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 152,044 control chromosomes in the GnomAD database, including 37,831 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 0.70 (37831 hom., cov: 31)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.420
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.3720-4466A>G		intron_variant	Intron 25 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.3720-4466A>G		intron_variant	Intron 25 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.3663-4466A>G		intron_variant	Intron 24 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.3720-4466A>G		intron_variant	Intron 25 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.3663-4466A>G		intron_variant	Intron 24 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106929 AN: 151926 Hom.: 37803 Cov.: 31

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.684

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

GnomAD4 genome AF: 0.704 AC: 107006 AN: 152044 Hom.: 37831 Cov.: 31 AF XY: 0.708 AC XY: 52608 AN XY: 74308

African (AFR) AF: 0.639 AC: 26484 AN: 41448

American (AMR) AF: 0.662 AC: 10112 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2636 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4059 AN: 5152

South Asian (SAS) AF: 0.787 AC: 3786 AN: 4810

European-Finnish (FIN) AF: 0.736 AC: 7803 AN: 10596

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.731 AC: 49711 AN: 67980

Other (OTH) AF: 0.687 AC: 1453 AN: 2116

Alfa AF: 0.718 Hom.: 66212

Bravo AF: 0.691

Asia WGS AF: 0.743 AC: 2586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.77
PhyloP100		0.42
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: rs3753748; hg19: chr1-181715146;