1-181703546-T-G

Variant names:

• chr1-181703546-T-G
• rs7513540
• NM_001205293.3:c.1056-7408T>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.1056-7408T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 152,008 control chromosomes in the GnomAD database, including 30,602 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 0.62 (30602 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 3 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.1056-7408T>G		intron_variant	Intron 7 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.1056-7408T>G		intron_variant	Intron 7 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.1056-7408T>G		intron_variant	Intron 7 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.1056-7408T>G		intron_variant	Intron 7 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.1056-7408T>G		intron_variant	Intron 7 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.1491-7408T>G		intron_variant	Intron 9 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94226 AN: 151890 Hom.: 30592 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.605

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

GnomAD4 genome AF: 0.620 AC: 94259 AN: 152008 Hom.: 30602 Cov.: 32 AF XY: 0.624 AC XY: 46384 AN XY: 74310

African (AFR) AF: 0.416 AC: 17233 AN: 41444

American (AMR) AF: 0.600 AC: 9152 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2536 AN: 3472

East Asian (EAS) AF: 0.789 AC: 4085 AN: 5180

South Asian (SAS) AF: 0.656 AC: 3153 AN: 4806

European-Finnish (FIN) AF: 0.708 AC: 7475 AN: 10560

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48413 AN: 67972

Other (OTH) AF: 0.609 AC: 1282 AN: 2104

Alfa AF: 0.673 Hom.: 95046

Bravo AF: 0.602

Asia WGS AF: 0.650 AC: 2262 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	10
DANN	Benign	0.48
PhyloP100		1.3
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: rs7513540; hg19: chr1-181672682;