rs200092211

Positions:

chr2-152099007-G-A

Variant summary

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

The NM_000726.5(CACNB4):c.5C>T(p.Ser2Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,533,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 1 hom. )

Consequence

CACNB4
NM_000726.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 2.67

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:

(HGNC:):

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=0.016155422).

BP6

Variant 2-152099007-G-A is Benign according to our data. Variant chr2-152099007-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193120.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=4, Likely_benign=2}. Variant chr2-152099007-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB4	NM_000726.5 linkuse as main transcript	c.5C>T	p.Ser2Phe	missense_variant	1/14	ENST00000539935.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB4	ENST00000539935.7 linkuse as main transcript	c.5C>T	p.Ser2Phe	missense_variant	1/14	1	NM_000726.5		O00305-1
	ENST00000420365.1 linkuse as main transcript	n.120+560G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00145

AC:

195

AN:

134704

Hom.:

AF XY:

0.00121

AC XY:

AN XY:

72796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000240

Gnomad FIN exome

AF:

0.0000663

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.000873

AC:

1206

AN:

1381012

Hom.:

Cov.:

AF XY:

0.000889

AC XY:

606

AN XY:

681524

show subpopulations

Gnomad4 AFR exome

AF:

0.000133

Gnomad4 AMR exome

AF:

0.00176

Gnomad4 ASJ exome

AF:

0.0100

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000299

Gnomad4 FIN exome

AF:

0.0000204

Gnomad4 NFE exome

AF:

0.000732

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.000907

AC:

138

AN:

152230

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000728

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2017	The S2F variant of unknown significance has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The 1000 Genomes Project reports S2F was observed in 1/214 alleles (0.5%) from individuals of Italian background (McVean et al., 2012). The S2F 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. This substitution alters a highly conserved position in the N-terminal region of the CACNB4 protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to date only a small number of substitutions in CACNB4 have been published in association with epilepsy, and no pathogenic variants have been reported in the N-terminal region of the protein (Escayg et al., 2000; Ohmori et al., 2008). Therefore, based on the currently available information, it is unclear whether S2F is a pathogenic or a rare benign variant. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2014	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CACNB4: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 04, 2015	- -

Epilepsy, idiopathic generalized, susceptibility to, 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 31, 2016

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

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

Episodic ataxia type 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Invitae

Nov 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.60

T;T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.81

L;.;.;L

MutationTaster

Benign

0.56

N;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.61

N;.;.;N

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Uncertain

0.0050

D;.;.;D

Polyphen

0.97

D;.;.;.

Vest4

0.47

MVP

0.87

MPC

1.7

ClinPred

0.18

GERP RS

2.7

Varity_R

0.22

gMVP

0.43

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