1-181717613-T-C

Variant names:

• chr1-181717613-T-C
• rs2253388
• NM_001205293.3:c.1525+311T>C

Variant summary

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

The NM_001205293.3(CACNA1E):​c.1525+311T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 151,942 control chromosomes in the GnomAD database, including 30,170 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 0.60 (30170 hom., cov: 30)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.1525+311T>C		intron_variant	Intron 11 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.1525+311T>C		intron_variant	Intron 11 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.1525+311T>C		intron_variant	Intron 11 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.1525+311T>C		intron_variant	Intron 11 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.1525+311T>C		intron_variant	Intron 11 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90882 AN: 151824 Hom.: 30149 Cov.: 30

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.766

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.599

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

GnomAD4 genome AF: 0.598 AC: 90927 AN: 151942 Hom.: 30170 Cov.: 30 AF XY: 0.604 AC XY: 44837 AN XY: 74240

African (AFR) AF: 0.283 AC: 11729 AN: 41424

American (AMR) AF: 0.661 AC: 10099 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2468 AN: 3470

East Asian (EAS) AF: 0.766 AC: 3928 AN: 5126

South Asian (SAS) AF: 0.654 AC: 3145 AN: 4808

European-Finnish (FIN) AF: 0.761 AC: 8021 AN: 10546

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

European-Non Finnish (NFE) AF: 0.727 AC: 49442 AN: 67968

Other (OTH) AF: 0.603 AC: 1273 AN: 2112

Alfa AF: 0.678 Hom.: 16510

Bravo AF: 0.576

Asia WGS AF: 0.666 AC: 2318 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		-0.17
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: rs2253388; hg19: chr1-181686749; COSMIC: COSV62386648; COSMIC: COSV62386648;