1-181483501-CTTTTTTTTTTTT-CTTTTTTTTTT

Variant names:

• chr1-181483501-CTT-C
• rs111237511
• ENST00000367570.6:c.-231_-230delTT

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
• Clinical Significance: Not reported in ClinVar
• 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: Illumina, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367570.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.-243_-242delTT		upstream_gene	N/A	NP_001192222.1	Q15878-1
	CACNA1E	NM_000721.4		c.-243_-242delTT		upstream_gene	N/A	NP_000712.2	Q15878-3
	CACNA1E	NM_001205294.2		c.-243_-242delTT		upstream_gene	N/A	NP_001192223.1	Q15878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367570.6	TSL:1	c.-231_-230delTT		5_prime_UTR	Exon 1 of 47	ENSP00000356542.1	Q15878-3
	CACNA1E	ENST00000524607.6	TSL:5	c.435-230_435-229delTT		intron	N/A	ENSP00000432038.2	E9PIE8
	CACNA1E	ENST00000533229.1	TSL:1	n.204_205delTT		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes AF: 0.000331 AC: 46 AN: 139176 Hom.: 0 Cov.: 29

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.: 0 AF XY: 0.0203 AC XY: 733 AN XY: 36110

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

African (AFR) AF: 0.0160 AC: 32 AN: 1994

American (AMR) AF: 0.0207 AC: 44 AN: 2124

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 65 AN: 2458

East Asian (EAS) AF: 0.0257 AC: 174 AN: 6782

South Asian (SAS) AF: 0.0104 AC: 15 AN: 1440

European-Finnish (FIN) AF: 0.0182 AC: 77 AN: 4232

Middle Eastern (MID) AF: 0.0242 AC: 10 AN: 414

European-Non Finnish (NFE) AF: 0.0205 AC: 931 AN: 45416

Other (OTH) AF: 0.0214 AC: 98 AN: 4584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000330 AC: 46 AN: 139208 Hom.: 0 Cov.: 29 AF XY: 0.000282 AC XY: 19 AN XY: 67454

African (AFR) AF: 0.00107 AC: 40 AN: 37442

American (AMR) AF: 0.000216 AC: 3 AN: 13904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4642

South Asian (SAS) AF: 0.00 AC: 0 AN: 4138

European-Finnish (FIN) AF: 0.000242 AC: 2 AN: 8266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64420

Other (OTH) AF: 0.00 AC: 0 AN: 1904

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;