Genetic Variant CACNA1E:n.203_205delTTT (chr1-181483501-CTTT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000367570.6(CACNA1E):c.-232_-230delTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 71,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1E
ENST00000367570.6 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.166

Publications

0 publications found

Variant links:

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

CACNA1E links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 link	c.-243_-241delTTT		upstream_gene_variant		ENST00000367573.7	NP_001192222.1	Q15878-1Q59FG1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1E	ENST00000367570.6 link	c.-232_-230delTTT	5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000524607.6 link	c.435-231_435-229delTTT	intron_variant	Intron 2 of 11	5		ENSP00000432038.2	E9PIE8
CACNA1E	ENST00000367573.7 link	c.-243_-241delTTT	upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 link	c.-243_-241delTTT	upstream_gene_variant		5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000621791.4 link	c.-243_-241delTTT	upstream_gene_variant		1		ENSP00000481619.1	Q15878-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

139210

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00253

AC:

180

AN:

71216

Hom.:

AF XY:

0.00294

AC XY:

109

AN XY:

37026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00291

AC:

AN:

2060

American (AMR)

AF:

0.00372

AC:

AN:

2148

Ashkenazi Jewish (ASJ)

AF:

0.00158

AC:

AN:

2530

East Asian (EAS)

AF:

0.00158

AC:

AN:

6946

South Asian (SAS)

AF:

0.00275

AC:

AN:

1452

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

4334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

428

European-Non Finnish (NFE)

AF:

0.00268

AC:

125

AN:

46618

Other (OTH)

AF:

0.00277

AC:

AN:

4700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

139242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67472

African (AFR)

AF:

0.00

AC:

AN:

37444

American (AMR)

AF:

0.00

AC:

AN:

13908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3344

East Asian (EAS)

AF:

0.00

AC:

AN:

4642

South Asian (SAS)

AF:

0.00

AC:

AN:

4138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64442

Other (OTH)

AF:

0.00

AC:

AN:

1906

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.17

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-181483501-CTTTTTTTTTTTT-CTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over