NM_001205293.3:c.5680-46C>T

Variant names:

• chr1-181785667-C-T
• rs473200
• NM_001205293.3:c.5680-46C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001205293.3(CACNA1E):​c.5680-46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,281,290 control chromosomes in the GnomAD database, including 26,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3205 hom., cov: 32)
  • Exomes 𝑓: 0.20 (23211 hom.)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.444
• Publications: 14 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=-0.82).
• BP6: Variant 1-181785667-C-T is Benign according to our data. Variant chr1-181785667-C-T is described in ClinVar as Benign. ClinVar VariationId is 1262703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.5680-46C>T		intron	N/A	NP_001192222.1
	CACNA1E	NM_000721.4		c.5680-46C>T		intron	N/A	NP_000712.2
	CACNA1E	NM_001205294.2		c.5623-46C>T		intron	N/A	NP_001192223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.5680-46C>T		intron	N/A	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.5623-46C>T		intron	N/A	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.5680-46C>T		intron	N/A	ENSP00000356542.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31021 AN: 152028 Hom.: 3201 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.219

GnomAD2 exomes AF: 0.210 AC: 51448 AN: 245516 AF XY: 0.215

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.273

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.197 AC: 221994 AN: 1129144 Hom.: 23211 Cov.: 15 AF XY: 0.201 AC XY: 115945 AN XY: 577752

African (AFR) AF: 0.214 AC: 5734 AN: 26776

American (AMR) AF: 0.163 AC: 7067 AN: 43284

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4241 AN: 24108

East Asian (EAS) AF: 0.236 AC: 9000 AN: 38118

South Asian (SAS) AF: 0.303 AC: 23888 AN: 78838

European-Finnish (FIN) AF: 0.200 AC: 10640 AN: 53232

Middle Eastern (MID) AF: 0.265 AC: 1369 AN: 5166

European-Non Finnish (NFE) AF: 0.185 AC: 150005 AN: 810126

Other (OTH) AF: 0.203 AC: 10050 AN: 49496

GnomAD4 genome AF: 0.204 AC: 31026 AN: 152146 Hom.: 3205 Cov.: 32 AF XY: 0.207 AC XY: 15396 AN XY: 74392

African (AFR) AF: 0.224 AC: 9291 AN: 41476

American (AMR) AF: 0.177 AC: 2701 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 602 AN: 3472

East Asian (EAS) AF: 0.246 AC: 1271 AN: 5172

South Asian (SAS) AF: 0.299 AC: 1444 AN: 4826

European-Finnish (FIN) AF: 0.199 AC: 2112 AN: 10598

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12775 AN: 67992

Other (OTH) AF: 0.219 AC: 462 AN: 2112

Alfa AF: 0.189 Hom.: 11998

Bravo AF: 0.202

Asia WGS AF: 0.251 AC: 870 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.7
DANN	Benign	0.67
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs473200; hg19: chr1-181754803; COSMIC: COSV62382745; COSMIC: COSV62382745;