rs200662010

Positions:

chr2-152098968-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000726.5(CACNB4):c.44C>G(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,529,042 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 8 hom. )

Consequence

CACNB4
NM_000726.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: -0.211

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:

CACNB4 (HGNC:):

CACNB4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069794953).

BP6

Variant 2-152098968-G-C is Benign according to our data. Variant chr2-152098968-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204939.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, Benign=3}. Variant chr2-152098968-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB4	NM_000726.5 linkuse as main transcript	c.44C>G	p.Pro15Arg	missense_variant	1/14	ENST00000539935.7	NP_000717.2	O00305-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7 linkuse as main transcript	c.44C>G	p.Pro15Arg	missense_variant	1/14	1	NM_000726.5	ENSP00000438949.1		O00305-1

Frequencies

GnomAD3 genomes

AF:

0.00190

AC:

289

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00344

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00149

AC:

203

AN:

135806

Hom.:

AF XY:

0.00155

AC XY:

113

AN XY:

73088

show subpopulations

Gnomad AFR exome

AF:

0.000395

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.000288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000201

Gnomad NFE exome

AF:

0.00324

Gnomad OTH exome

AF:

0.000805

GnomAD4 exome

AF:

0.00324

AC:

4461

AN:

1376946

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2172

AN XY:

678956

show subpopulations

Gnomad4 AFR exome

AF:

0.000531

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.000464

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.000326

Gnomad4 NFE exome

AF:

0.00396

Gnomad4 OTH exome

AF:

0.00246

GnomAD4 genome

AF:

0.00190

AC:

289

AN:

152096

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

115

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00344

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00258

Hom.:

Bravo

AF:

0.00206

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00103

AC:

ESP6500EA

AF:

0.00320

AC:

ExAC

AF:

0.00114

AC:

127

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2015	p.Pro15Arg (CCG>CGG): c.44 C>G in exon 1 of the CACNB4 gene (NM_000726.2). The P15R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI Exome Sequencing Project reports P15R was observed in 26/8128 (0.3%) alleles from individuals of European background, and the 1000 Genomes Project reports P15R was observed in 1/120 (0.8%) alleles from individuals of Mexican background, indicating it may be a rare (benign) variant in these populations. The P15R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution alters a poorly conserved position in the predicted N-terminal region of the CACNB4 protein, and disease-associated mutations have not been reported in this region to date (Escayg et al., 2000; Ohmori et al., 2008). Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 22, 2019	- -

Episodic ataxia type 5;C2750887:Epilepsy, idiopathic generalized, susceptibility to, 9

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 18, 2018	- -

Juvenile myoclonic epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

CACNB4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

CACNB4: BS1, BS2 -

Episodic ataxia type 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.087

T;.;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

N;.;.;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

N;.;.;N

REVEL

Benign

0.076

Sift

Uncertain

0.023

D;.;.;D

Sift4G

Benign

0.58

T;.;.;T

Polyphen

0.047

B;.;.;.

Vest4

0.16

MVP

0.76

MPC

0.66

ClinPred

0.016

GERP RS

-0.083

Varity_R

0.067

gMVP

0.45

Splicing

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