Genetic Variant NM_001205293.3:c.4008T>C (chr1-181755974-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001205293.3(CACNA1E):c.4008T>C(p.His1336His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,612,618 control chromosomes in the GnomAD database, including 65,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8285 hom., cov: 32)

Exomes 𝑓: 0.28 ( 57513 hom. )

Consequence

CACNA1E
NM_001205293.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.472

Publications

18 publications found

Variant links:

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

CACNA1E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 1-181755974-T-C is Benign according to our data. Variant chr1-181755974-T-C is described in ClinVar as Benign. ClinVar VariationId is 1192686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.472 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1E	NM_001205293.3	MANE Select	c.4008T>C	p.His1336His	synonymous	Exon 29 of 48	NP_001192222.1
CACNA1E	NM_000721.4		c.4008T>C	p.His1336His	synonymous	Exon 29 of 47	NP_000712.2
CACNA1E	NM_001205294.2		c.3951T>C	p.His1317His	synonymous	Exon 28 of 46	NP_001192223.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.4008T>C	p.His1336His	synonymous	Exon 29 of 48	ENSP00000356545.2
CACNA1E	ENST00000360108.7	TSL:5	c.3951T>C	p.His1317His	synonymous	Exon 28 of 47	ENSP00000353222.3
CACNA1E	ENST00000367570.6	TSL:1	c.4008T>C	p.His1336His	synonymous	Exon 29 of 47	ENSP00000356542.1

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48551

AN:

151846

Hom.:

8266

Cov.:

show subpopulations

Gnomad AFR

AF:

0.445

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.322

Gnomad ASJ

AF:

0.226

Gnomad EAS

AF:

0.0658

Gnomad SAS

AF:

0.360

Gnomad FIN

AF:

0.264

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.323

GnomAD2 exomes

AF:

0.282

AC:

70281

AN:

248782

AF XY:

0.283

show subpopulations

Gnomad AFR exome

AF:

0.456

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.0584

Gnomad FIN exome

AF:

0.263

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.281

GnomAD4 exome

AF:

0.275

AC:

401762

AN:

1460654

Hom.:

57513

Cov.:

AF XY:

0.278

AC XY:

201778

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.452

AC:

15117

AN:

33462

American (AMR)

AF:

0.320

AC:

14297

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6346

AN:

26128

East Asian (EAS)

AF:

0.0594

AC:

2357

AN:

39692

South Asian (SAS)

AF:

0.371

AC:

31991

AN:

86206

European-Finnish (FIN)

AF:

0.261

AC:

13918

AN:

53376

Middle Eastern (MID)

AF:

0.356

AC:

2051

AN:

5764

European-Non Finnish (NFE)

AF:

0.269

AC:

298452

AN:

1111032

Other (OTH)

AF:

0.286

AC:

17233

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

14193

28386

42578

56771

70964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10072

20144

30216

40288

50360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.320

AC:

48600

AN:

151964

Hom.:

8285

Cov.:

AF XY:

0.318

AC XY:

23596

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.445

AC:

18436

AN:

41430

American (AMR)

AF:

0.322

AC:

4916

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.226

AC:

783

AN:

3464

East Asian (EAS)

AF:

0.0649

AC:

336

AN:

5174

South Asian (SAS)

AF:

0.359

AC:

1729

AN:

4810

European-Finnish (FIN)

AF:

0.264

AC:

2787

AN:

10544

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.273

AC:

18561

AN:

67964

Other (OTH)

AF:

0.322

AC:

679

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1667

3334

5002

6669

8336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.292

Hom.:

10808

Bravo

AF:

0.327

Asia WGS

AF:

0.210

AC:

728

AN:

3478

EpiCase

AF:

0.273

EpiControl

AF:

0.272

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Developmental and epileptic encephalopathy, 69

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.52

CADD

Benign

2.5

(source)

DANN

Benign

0.67

PhyloP100

-0.47

Mutation Taster

=64/36

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over