rs61736804

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

ENSG00000283228 (HGNC:):

ENSG00000283228 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 128563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151860817-A-T is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.0314

AC:

7809

AN:

249040

Hom.:

205

AF XY:

0.0311

AC XY:

4196

AN XY:

135102

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 SAS exome

AF:

0.0325

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

Gnomad4 AFR exome

AF:

0.125

Gnomad4 AMR exome

AF:

0.0171

Gnomad4 ASJ exome

AF:

0.0605

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.0321

Gnomad4 FIN exome

AF:

0.0199

Gnomad4 NFE exome

AF:

0.0273

Gnomad4 OTH exome

AF:

0.0357

GnomAD4 genome

AF:

0.0531

AC:

8076

AN:

152202

Hom.:

340

Cov.:

AF XY:

0.0516

AC XY:

3838

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.120

Gnomad4 AMR

AF:

0.0328

Gnomad4 ASJ

AF:

0.0533

Gnomad4 EAS

AF:

0.00367

Gnomad4 SAS

AF:

0.0262

Gnomad4 FIN

AF:

0.0213

Gnomad4 NFE

AF:

0.0273

Gnomad4 OTH

AF:

0.0507

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.2

DANN

Benign

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over