rs111830180

Variant names:

• chr1-181483507-T-C
• rs111830180
• ENST00000533229.1:n.197T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-181483507-T-C
• chr1-181483507-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000367570.6(CACNA1E):​c.-238T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00652 in 344,416 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: CACNA1E ENST00000367570.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.56
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-181483507-T-C is Benign according to our data. Variant chr1-181483507-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1300371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1974/151380) while in subpopulation AFR AF = 0.0447 (1840/41146). AF 95% confidence interval is 0.043. There are 44 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1974 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.-238T>C		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.-238T>C		5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000524607.6	c.435-237T>C		intron_variant	Intron 2 of 11	5		ENSP00000432038.2
CACNA1E	ENST00000367573.7	c.-238T>C		upstream_gene_variant		1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.-238T>C		upstream_gene_variant		5		ENSP00000353222.3
CACNA1E	ENST00000621791.4	c.-238T>C		upstream_gene_variant		1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1970 AN: 151264 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00604

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.0106

GnomAD4 exome AF: 0.00141 AC: 272 AN: 193036 Hom.: 9 Cov.: 0 AF XY: 0.00116 AC XY: 114 AN XY: 98264

African (AFR) AF: 0.0361 AC: 187 AN: 5182

American (AMR) AF: 0.00262 AC: 15 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: 0.00 AC: 0 AN: 1060

European-Non Finnish (NFE) AF: 0.000176 AC: 22 AN: 124990

Other (OTH) AF: 0.00370 AC: 48 AN: 12980

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 151380 Hom.: 44 Cov.: 31 AF XY: 0.0123 AC XY: 907 AN XY: 73996

African (AFR) AF: 0.0447 AC: 1840 AN: 41146

American (AMR) AF: 0.00604 AC: 92 AN: 15240

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

East Asian (EAS) AF: 0.000194 AC: 1 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: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67814

Other (OTH) AF: 0.0105 AC: 22 AN: 2094

Alfa AF: 0.0780 Hom.: 164

Bravo AF: 0.0151

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 30, 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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.097
DANN	Benign	0.29
PhyloP100		-1.6
PromoterAI		-0.021	Neutral

Splicing

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

Other links and lift over

dbSNP: rs111830180; hg19: chr1-181452643;