rs375048675

Variant names:

• chr1-181483507-T-TTC
• rs375048675
• ENST00000367570.6:c.-237_-236insCT

Variant summary

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

The ENST00000367570.6(CACNA1E):​c.-237_-236insCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 344,410 control chromosomes in the GnomAD database, including 349 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (291 hom., cov: 30)
  • Exomes 𝑓: 0.0037 (58 hom.)
• Consequence: CACNA1E ENST00000367570.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0920
• 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, Illumina, 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-181483507-T-TTC is Benign according to our data. Variant chr1-181483507-T-TTC is described in ClinVar as Benign. ClinVar VariationId is 1238863.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

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.-238_-237insTC		upstream_gene	N/A	NP_001192222.1	Q15878-1
	CACNA1E	NM_000721.4		c.-238_-237insTC		upstream_gene	N/A	NP_000712.2	Q15878-3
	CACNA1E	NM_001205294.2		c.-238_-237insTC		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.-237_-236insCT		5_prime_UTR	Exon 1 of 47	ENSP00000356542.1	Q15878-3
	CACNA1E	ENST00000524607.6	TSL:5	c.435-236_435-235insCT		intron	N/A	ENSP00000432038.2	E9PIE8
	CACNA1E	ENST00000533229.1	TSL:1	n.198_199insCT		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4958 AN: 151264 Hom.: 291 Cov.: 30

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000546

Gnomad OTH AF: 0.0251

GnomAD4 exome AF: 0.00373 AC: 720 AN: 193030 Hom.: 58 Cov.: 0 AF XY: 0.00326 AC XY: 320 AN XY: 98262

African (AFR) AF: 0.0958 AC: 496 AN: 5178

American (AMR) AF: 0.00872 AC: 50 AN: 5732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7354

East Asian (EAS) AF: 0.00 AC: 0 AN: 17306

South Asian (SAS) AF: 0.00 AC: 0 AN: 2534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15898

Middle Eastern (MID) AF: 0.00377 AC: 4 AN: 1060

European-Non Finnish (NFE) AF: 0.000344 AC: 43 AN: 124990

Other (OTH) AF: 0.00979 AC: 127 AN: 12978

GnomAD4 genome AF: 0.0329 AC: 4973 AN: 151380 Hom.: 291 Cov.: 30 AF XY: 0.0322 AC XY: 2382 AN XY: 73994

African (AFR) AF: 0.112 AC: 4613 AN: 41146

American (AMR) AF: 0.0175 AC: 266 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000546 AC: 37 AN: 67814

Other (OTH) AF: 0.0248 AC: 52 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.092

Splicing

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

Other links and lift over

dbSNP: rs375048675; hg19: chr1-181452643;