rs556321

Variant names:

• chr1-181484373-T-C
• rs556321
• NM_001205293.3:c.266+363T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-181484373-T-C
• chr1-181484373-T-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.266+363T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,040 control chromosomes in the GnomAD database, including 2,925 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 0.19 (2925 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.812
• Publications: 12 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.266+363T>C		intron_variant	Intron 1 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.266+363T>C		intron_variant	Intron 1 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.266+363T>C		intron_variant	Intron 1 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.266+363T>C		intron_variant	Intron 1 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.266+363T>C		intron_variant	Intron 1 of 45	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.701+363T>C		intron_variant	Intron 3 of 11	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28807 AN: 151922 Hom.: 2918 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0965

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.190 AC: 28856 AN: 152040 Hom.: 2925 Cov.: 32 AF XY: 0.184 AC XY: 13668 AN XY: 74328

African (AFR) AF: 0.261 AC: 10810 AN: 41428

American (AMR) AF: 0.178 AC: 2720 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1016 AN: 5146

South Asian (SAS) AF: 0.0962 AC: 464 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1238 AN: 10590

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11400 AN: 67974

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.159 Hom.: 1540

Bravo AF: 0.209

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	12
DANN	Benign	0.53
PhyloP100		0.81
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: rs556321; hg19: chr1-181453509;