1-181483501-CTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

• chr1-181483501-CT-C
• rs111237511
• ENST00000533229.1:n.205delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000367570.6(CACNA1E):​c.-230delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 208,618 control chromosomes in the GnomAD database, including 123 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (112 hom., cov: 29)
  • Exomes 𝑓: 0.21 (11 hom.)
• Consequence: CACNA1E ENST00000367570.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 1-181483501-CT-C is Benign according to our data. Variant chr1-181483501-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1320658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.-243delT		upstream_gene_variant		ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367570.6	c.-230delT		5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000524607.6	c.435-229delT		intron_variant	Intron 2 of 11	5		ENSP00000432038.2
CACNA1E	ENST00000367573.7	c.-243delT		upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.-243delT		upstream_gene_variant		5		ENSP00000353222.3
CACNA1E	ENST00000621791.4	c.-243delT		upstream_gene_variant		1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4528 AN: 139036 Hom.: 112 Cov.: 29

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.0218

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.0235

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0338

GnomAD4 exome AF: 0.209 AC: 14541 AN: 69550 Hom.: 11 Cov.: 0 AF XY: 0.210 AC XY: 7595 AN XY: 36138

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

African (AFR) AF: 0.140 AC: 283 AN: 2022

American (AMR) AF: 0.215 AC: 455 AN: 2112

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 544 AN: 2448

East Asian (EAS) AF: 0.263 AC: 1780 AN: 6764

South Asian (SAS) AF: 0.131 AC: 189 AN: 1438

European-Finnish (FIN) AF: 0.191 AC: 808 AN: 4228

Middle Eastern (MID) AF: 0.203 AC: 86 AN: 424

European-Non Finnish (NFE) AF: 0.208 AC: 9456 AN: 45520

Other (OTH) AF: 0.205 AC: 940 AN: 4594

⚠️ 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.

GnomAD4 genome AF: 0.0326 AC: 4536 AN: 139068 Hom.: 112 Cov.: 29 AF XY: 0.0337 AC XY: 2271 AN XY: 67370

African (AFR) AF: 0.0219 AC: 821 AN: 37418

American (AMR) AF: 0.0598 AC: 831 AN: 13886

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 73 AN: 3342

East Asian (EAS) AF: 0.135 AC: 628 AN: 4642

South Asian (SAS) AF: 0.0590 AC: 244 AN: 4136

European-Finnish (FIN) AF: 0.0268 AC: 221 AN: 8252

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.0256 AC: 1647 AN: 64342

Other (OTH) AF: 0.0336 AC: 64 AN: 1902

Alfa AF: 0.00367 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

dbSNP: rs111237511; hg19: chr1-181452637;