Genetic Variant CACNA1E:n.204_205delTT (chr1-181483501-CTT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000367570.6(CACNA1E):c.-231_-230delTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00715 in 208,652 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: 𝑓 0.00033 ( 0 hom., cov: 29)

Exomes 𝑓: 0.021 ( 0 hom. )

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3 link	c.-243_-242delTT		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.-231_-230delTT	5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1	Q15878-3
CACNA1E	ENST00000524607.6 link	c.435-230_435-229delTT	intron_variant	Intron 2 of 11	5		ENSP00000432038.2	E9PIE8
CACNA1E	ENST00000367573.7 link	c.-243_-242delTT	upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2	Q15878-1
CACNA1E	ENST00000360108.7 link	c.-243_-242delTT	upstream_gene_variant		5		ENSP00000353222.3	F8W9Z1
CACNA1E	ENST00000621791.4 link	c.-243_-242delTT	upstream_gene_variant		1		ENSP00000481619.1	Q15878-2

Frequencies

GnomAD3 genomes

AF:

0.000331

AC:

AN:

139176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000242

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0208

AC:

1446

AN:

69444

Hom.:

AF XY:

0.0203

AC XY:

733

AN XY:

36110

show subpopulations

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

African (AFR)

AF:

0.0160

AC:

AN:

1994

American (AMR)

AF:

0.0207

AC:

AN:

2124

Ashkenazi Jewish (ASJ)

AF:

0.0264

AC:

AN:

2458

East Asian (EAS)

AF:

0.0257

AC:

174

AN:

6782

South Asian (SAS)

AF:

0.0104

AC:

AN:

1440

European-Finnish (FIN)

AF:

0.0182

AC:

AN:

4232

Middle Eastern (MID)

AF:

0.0242

AC:

AN:

414

European-Non Finnish (NFE)

AF:

0.0205

AC:

931

AN:

45416

Other (OTH)

AF:

0.0214

AC:

AN:

4584

⚠️ 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: 0.271

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000330

AC:

AN:

139208

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

67454

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

37442

American (AMR)

AF:

0.000216

AC:

AN:

13904

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:

0.000242

AC:

AN:

8266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64420

Other (OTH)

AF:

0.00

AC:

AN:

1904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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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chr1-181483501-CTT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over