Genetic Variant ENST00000533229.1:n.201_205delTTTTT (chr1-181483501-CTTTTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000533229.1(CACNA1E):n.201_205delTTTTT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 71,604 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CACNA1E
ENST00000533229.1 non_coding_transcript_exon

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 link	c.-243_-239delTTTTT		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.-234_-230delTTTTT	5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000524607.6 link	c.435-233_435-229delTTTTT	intron_variant	Intron 2 of 11	5		ENSP00000432038.2	E9PIE8
CACNA1E	ENST00000367573.7 link	c.-243_-239delTTTTT	upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 link	c.-243_-239delTTTTT	upstream_gene_variant		5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000621791.4 link	c.-243_-239delTTTTT	upstream_gene_variant		1		ENSP00000481619.1	Q15878-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000140

AC:

AN:

71604

Hom.:

AF XY:

0.0000269

AC XY:

AN XY:

37238

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

2064

American (AMR)

AF:

0.00

AC:

AN:

2162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2544

East Asian (EAS)

AF:

0.00

AC:

AN:

6984

South Asian (SAS)

AF:

0.00

AC:

AN:

1458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

434

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

46876

Other (OTH)

AF:

0.000212

AC:

AN:

4728

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.17

Splicing

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

Publications

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ENST00000533229.1:n.201_205delTTTTT

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