rs61736804

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000726.5(CACNB4):c.762T>A(p.Ile254Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.0318 in 1,594,974 control chromosomes in the GnomAD database, including 1,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 340 hom., cov: 32)

Exomes 𝑓: 0.030 ( 891 hom. )

Consequence

CACNB4
NM_000726.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.09

Publications

7 publications found

Variant links:

Genes affected

CACNB4 (HGNC:1404): (calcium voltage-gated channel auxiliary subunit beta 4) This gene encodes a member of the beta subunit family of voltage-dependent calcium channel complex proteins. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. The protein encoded by this locus plays an important role in calcium channel function by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Certain mutations in this gene have been associated with idiopathic generalized epilepsy (IGE), juvenile myoclonic epilepsy (JME), and episodic ataxia, type 5. [provided by RefSeq, Aug 2016]

CACNB4 Gene-Disease associations (from GenCC):

episodic ataxia type 5
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
juvenile myoclonic epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, idiopathic generalized, susceptibility to, 9
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNB4 links:

ENSG00000283228 (HGNC:):

ENSG00000283228 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-151860817-A-T is Benign according to our data. Variant chr2-151860817-A-T is described in ClinVar as Benign. ClinVar VariationId is 128563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB4	NM_000726.5 link	c.762T>A	p.Ile254Ile	synonymous_variant	Exon 10 of 14	ENST00000539935.7	NP_000717.2	O00305-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7 link	c.762T>A	p.Ile254Ile	synonymous_variant	Exon 10 of 14	1	NM_000726.5	ENSP00000438949.1		O00305-1
ENSG00000283228	ENST00000637559.1 link	n.598-5442T>A		intron_variant	Intron 7 of 11	5		ENSP00000489697.1		A0A1B0GTH0

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

8057

AN:

152084

Hom.:

337

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0329

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.0253

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0314

AC:

7809

AN:

249040

AF XY:

0.0311

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.0159

Gnomad ASJ exome

AF:

0.0599

Gnomad EAS exome

AF:

0.00389

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0276

Gnomad OTH exome

AF:

0.0270

GnomAD4 exome

AF:

0.0295

AC:

42569

AN:

1442772

Hom.:

891

Cov.:

AF XY:

0.0294

AC XY:

21104

AN XY:

719010

show subpopulations

African (AFR)

AF:

0.125

AC:

4128

AN:

33028

American (AMR)

AF:

0.0171

AC:

764

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

1572

AN:

26002

East Asian (EAS)

AF:

0.00169

AC:

AN:

39584

South Asian (SAS)

AF:

0.0321

AC:

2757

AN:

85890

European-Finnish (FIN)

AF:

0.0199

AC:

1060

AN:

53382

Middle Eastern (MID)

AF:

0.0383

AC:

218

AN:

5692

European-Non Finnish (NFE)

AF:

0.0273

AC:

29867

AN:

1094728

Other (OTH)

AF:

0.0357

AC:

2136

AN:

59770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1931

3862

5792

7723

9654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1170

2340

3510

4680

5850

<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:

0.0531

AC:

8076

AN:

152202

Hom.:

340

Cov.:

AF XY:

0.0516

AC XY:

3838

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.120

AC:

4990

AN:

41492

American (AMR)

AF:

0.0328

AC:

502

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

185

AN:

3470

East Asian (EAS)

AF:

0.00367

AC:

AN:

5184

South Asian (SAS)

AF:

0.0262

AC:

126

AN:

4818

European-Finnish (FIN)

AF:

0.0213

AC:

226

AN:

10614

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0273

AC:

1854

AN:

68014

Other (OTH)

AF:

0.0507

AC:

107

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

388

777

1165

1554

1942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0371

Hom.:

Bravo

AF:

0.0569

Asia WGS

AF:

0.0230

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Nov 16, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Juvenile myoclonic epilepsy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic ataxia type 5

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Idiopathic generalized epilepsy

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.2

(source)

DANN

Benign

0.86

PhyloP100

4.1

PromoterAI

-0.023

Neutral

(source)

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over