rs199922

Variant names:

• chr1-181765897-A-G
• rs199922
• NM_001205293.3:c.4816-649A>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.4816-649A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,262 control chromosomes in the GnomAD database, including 1,353 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 0.13 (1353 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.854
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.4816-649A>G		intron_variant	Intron 34 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.4816-649A>G		intron_variant	Intron 34 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.4759-649A>G		intron_variant	Intron 33 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.4816-649A>G		intron_variant	Intron 34 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.4759-649A>G		intron_variant	Intron 33 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20141 AN: 152144 Hom.: 1352 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.132 AC: 20130 AN: 152262 Hom.: 1353 Cov.: 32 AF XY: 0.134 AC XY: 9945 AN XY: 74454

African (AFR) AF: 0.138 AC: 5724 AN: 41532

American (AMR) AF: 0.128 AC: 1952 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 439 AN: 3472

East Asian (EAS) AF: 0.0448 AC: 232 AN: 5184

South Asian (SAS) AF: 0.238 AC: 1148 AN: 4824

European-Finnish (FIN) AF: 0.110 AC: 1170 AN: 10610

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8919 AN: 68028

Other (OTH) AF: 0.145 AC: 307 AN: 2110

Alfa AF: 0.138 Hom.: 697

Bravo AF: 0.131

Asia WGS AF: 0.122 AC: 421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.6
DANN	Benign	0.53
PhyloP100		0.85
Mutation Taster		=99/1	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: rs199922; hg19: chr1-181735033;