1-181483501-CTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000367570.6(CACNA1E):​c.-230dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 210,186 control chromosomes in the GnomAD database, including 62 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 29)
  • Exomes 𝑓: 0.057 (0 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-C-CT is Benign according to our data. Variant chr1-181483501-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 1300505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0253 (3522/139166) while in subpopulation AFR AF = 0.0485 (1814/37422). AF 95% confidence interval is 0.0466. There are 62 homozygotes in GnomAd4. There are 1660 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.-244_-243insT		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.-230dupT		5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000524607.6	c.435-229dupT		intron_variant	Intron 2 of 11	5		ENSP00000432038.2
CACNA1E	ENST00000367573.7	c.-244_-243insT		upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.-244_-243insT		upstream_gene_variant		5		ENSP00000353222.3
CACNA1E	ENST00000621791.4	c.-244_-243insT		upstream_gene_variant		1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3516 AN: 139134 Hom.: 62 Cov.: 29

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.0365

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0284

Gnomad EAS AF: 0.00601

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0185

GnomAD4 exome AF: 0.0566 AC: 4019 AN: 71020 Hom.: 0 Cov.: 0 AF XY: 0.0574 AC XY: 2118 AN XY: 36896

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

African (AFR) AF: 0.0647 AC: 132 AN: 2040

American (AMR) AF: 0.0568 AC: 122 AN: 2146

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 190 AN: 2526

East Asian (EAS) AF: 0.0412 AC: 286 AN: 6934

South Asian (SAS) AF: 0.0227 AC: 33 AN: 1454

European-Finnish (FIN) AF: 0.0535 AC: 232 AN: 4336

Middle Eastern (MID) AF: 0.0488 AC: 21 AN: 430

European-Non Finnish (NFE) AF: 0.0588 AC: 2730 AN: 46462

Other (OTH) AF: 0.0582 AC: 273 AN: 4692

⚠️ 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: 0.0253 AC: 3522 AN: 139166 Hom.: 62 Cov.: 29 AF XY: 0.0246 AC XY: 1660 AN XY: 67432

African (AFR) AF: 0.0485 AC: 1814 AN: 37422

American (AMR) AF: 0.0147 AC: 204 AN: 13906

Ashkenazi Jewish (ASJ) AF: 0.0284 AC: 95 AN: 3342

East Asian (EAS) AF: 0.00582 AC: 27 AN: 4642

South Asian (SAS) AF: 0.0128 AC: 53 AN: 4136

European-Finnish (FIN) AF: 0.0110 AC: 91 AN: 8266

Middle Eastern (MID) AF: 0.0184 AC: 5 AN: 272

European-Non Finnish (NFE) AF: 0.0181 AC: 1166 AN: 64398

Other (OTH) AF: 0.0184 AC: 35 AN: 1906

Alfa AF: 0.00192 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;