rs199923

Variant names:

• chr1-181765908-G-A
• rs199923
• NM_001205293.3:c.4816-638G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-181765908-G-A
• chr1-181765908-G-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.4816-638G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,156 control chromosomes in the GnomAD database, including 4,880 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 0.25 (4880 hom., cov: 32)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.957
• Publications: 4 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.4816-638G>A		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.4816-638G>A		intron_variant	Intron 34 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.4759-638G>A		intron_variant	Intron 33 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.4816-638G>A		intron_variant	Intron 34 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.4759-638G>A		intron_variant	Intron 33 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38256 AN: 152040 Hom.: 4874 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0649

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.275

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

GnomAD4 genome AF: 0.252 AC: 38271 AN: 152156 Hom.: 4880 Cov.: 32 AF XY: 0.251 AC XY: 18658 AN XY: 74396

African (AFR) AF: 0.255 AC: 10600 AN: 41490

American (AMR) AF: 0.284 AC: 4341 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 619 AN: 3470

East Asian (EAS) AF: 0.0640 AC: 332 AN: 5184

South Asian (SAS) AF: 0.335 AC: 1613 AN: 4820

European-Finnish (FIN) AF: 0.240 AC: 2541 AN: 10584

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17315 AN: 68004

Other (OTH) AF: 0.273 AC: 575 AN: 2108

Alfa AF: 0.179 Hom.: 460

Bravo AF: 0.252

Asia WGS AF: 0.188 AC: 652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.55
PhyloP100		0.96
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: rs199923; hg19: chr1-181735044;