rs542973906

Positions:

chr2-152099004-G-A

Variant summary

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

The NM_000726.5(CACNB4):c.8C>T(p.Ser3Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,535,312 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.00023 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

CACNB4
NM_000726.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.931

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=0.02147293).

BP6

Variant 2-152099004-G-A is Benign according to our data. Variant chr2-152099004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204938.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}. Variant chr2-152099004-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB4	NM_000726.5 linkuse as main transcript	c.8C>T	p.Ser3Phe	missense_variant	1/14	ENST00000539935.7	NP_000717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7 linkuse as main transcript	c.8C>T	p.Ser3Phe	missense_variant	1/14	1	NM_000726.5	ENSP00000438949		O00305-1
	ENST00000420365.1 linkuse as main transcript	n.120+557G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000269

AC:

AN:

137724

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

74330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000507

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000284

Gnomad FIN exome

AF:

0.0000660

Gnomad NFE exome

AF:

0.000457

Gnomad OTH exome

AF:

0.000263

GnomAD4 exome

AF:

0.000299

AC:

413

AN:

1383066

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

198

AN XY:

682540

show subpopulations

Gnomad4 AFR exome

AF:

0.0000330

Gnomad4 AMR exome

AF:

0.0000326

Gnomad4 ASJ exome

AF:

0.000413

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000402

Gnomad4 FIN exome

AF:

0.000102

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000420

GnomAD4 genome

AF:

0.000230

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000292

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.000112

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2014	p.Ser3Phe (TCC>TTC): c.8 C>T in exon 1 of the CACNB4 gene (NM_000726.2). The S3F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S3F 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 occurs at a position that is not conserved across species in the N-terminal region of the CACNB4 protein. Additionally, to date only a small number of substitutions in CACNB4 have been published in association with epilepsy, and no disease-associated mutations have been reported in the N-terminal region of the protein (Excayg et al., 2000; Ohmori et al., 2008). 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 INFANT-EPI panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CACNB4: BS1 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.8C>T (p.S3F) alteration is located in exon 1 (coding exon 1) of the CACNB4 gene. This alteration results from a C to T substitution at nucleotide position 8, causing the serine (S) at amino acid position 3 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 204938). This variant has not been reported in the literature in individuals affected with CACNB4-related conditions. This variant is present in population databases (rs542973906, gnomAD 0.05%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 3 of the CACNB4 protein (p.Ser3Phe). -

Juvenile myoclonic epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

T;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.59

T;T;T;T

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.34

N;.;.;N

MutationTaster

Benign

0.78

N;N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.22

N;.;.;N

REVEL

Benign

0.19

Sift

Benign

0.055

T;.;.;T

Sift4G

Benign

0.12

T;.;.;T

Polyphen

0.42

B;.;.;.

Vest4

0.37

MVP

0.85

MPC

0.79

ClinPred

0.11

GERP RS

3.5

Varity_R

0.11

gMVP

0.36

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