1-181483501-C-CTTT

Variant names:

• chr1-181483501-C-CTTT
• rs111237511
• ENST00000367570.6:c.-232_-230dupTTT

Variant summary

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

The ENST00000367570.6(CACNA1E):​c.-232_-230dupTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 210,814 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (15 hom., cov: 29)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CACNA1E ENST00000367570.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-181483501-C-CTTT is Benign according to our data. Variant chr1-181483501-C-CTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1301079.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00798 (1111/139218) while in subpopulation AFR AF = 0.0286 (1069/37418). AF 95% confidence interval is 0.0271. There are 15 homozygotes in GnomAd4. There are 494 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.-244_-243insTTT		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.-232_-230dupTTT		5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000524607.6	c.435-231_435-229dupTTT		intron_variant	Intron 2 of 11	5		ENSP00000432038.2
CACNA1E	ENST00000367573.7	c.-244_-243insTTT		upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.-244_-243insTTT		upstream_gene_variant		5		ENSP00000353222.3
CACNA1E	ENST00000621791.4	c.-244_-243insTTT		upstream_gene_variant		1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1110 AN: 139186 Hom.: 15 Cov.: 29

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000241

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000931

Gnomad OTH AF: 0.00369

GnomAD4 exome AF: 0.000265 AC: 19 AN: 71596 Hom.: 0 Cov.: 0 AF XY: 0.000242 AC XY: 9 AN XY: 37238

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

African (AFR) AF: 0.00533 AC: 11 AN: 2062

American (AMR) AF: 0.00 AC: 0 AN: 2164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2544

East Asian (EAS) AF: 0.000143 AC: 1 AN: 6984

South Asian (SAS) AF: 0.00 AC: 0 AN: 1458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 432

European-Non Finnish (NFE) AF: 0.0000640 AC: 3 AN: 46870

Other (OTH) AF: 0.000846 AC: 4 AN: 4728

⚠️ 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: 0.00798 AC: 1111 AN: 139218 Hom.: 15 Cov.: 29 AF XY: 0.00732 AC XY: 494 AN XY: 67458

African (AFR) AF: 0.0286 AC: 1069 AN: 37418

American (AMR) AF: 0.00201 AC: 28 AN: 13906

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

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

South Asian (SAS) AF: 0.000242 AC: 1 AN: 4138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8274

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

European-Non Finnish (NFE) AF: 0.0000931 AC: 6 AN: 64442

Other (OTH) AF: 0.00367 AC: 7 AN: 1906

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 28, 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

Publications

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Other links and lift over

dbSNP: rs111237511; hg19: chr1-181452637;