rs200662010

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P15P) has been classified as Likely benign.

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

Publications

1 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: Labcorp Genetics (formerly Invitae), G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNB4 links:

ENSG00000225214 (HGNC:):

ENSG00000225214 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 204939.

BS2

High AC in GnomAd4 at 289 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000726.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNB4	NM_000726.5	MANE Select	c.44C>G	p.Pro15Arg	missense	Exon 1 of 14	NP_000717.2	O00305-1
CACNB4	NM_001145798.2		c.44C>G	p.Pro15Arg	missense	Exon 1 of 13	NP_001139270.1	O00305-4
CACNB4	NM_001005746.4		c.-319C>G		upstream_gene	N/A	NP_001005746.1	O00305-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.44C>G	p.Pro15Arg	missense	Exon 1 of 14	ENSP00000438949.1	O00305-1
CACNB4	ENST00000201943.10	TSL:1	c.44C>G	p.Pro15Arg	missense	Exon 1 of 13	ENSP00000201943.5	O00305-4
CACNB4	ENST00000427385.6	TSL:5	c.44C>G	p.Pro15Arg	missense	Exon 1 of 13	ENSP00000410978.2	A0A1C7CYX2

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

GnomAD2 exomes

AF:

0.00149

AC:

203

AN:

135806

AF XY:

0.00155

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 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

African (AFR)

AF:

0.000531

AC:

AN:

30156

American (AMR)

AF:

0.00109

AC:

AN:

28554

Ashkenazi Jewish (ASJ)

AF:

0.000464

AC:

AN:

23716

East Asian (EAS)

AF:

0.00

AC:

AN:

35132

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76166

European-Finnish (FIN)

AF:

0.000326

AC:

AN:

49090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4752

European-Non Finnish (NFE)

AF:

0.00396

AC:

4246

AN:

1072478

Other (OTH)

AF:

0.00246

AC:

140

AN:

56902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

194

388

581

775

969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.00190

AC:

289

AN:

152096

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

115

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

41506

American (AMR)

AF:

0.00144

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00344

AC:

234

AN:

67950

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00258

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Episodic ataxia type 5;C2750887:Epilepsy, idiopathic generalized, susceptibility to, 9 (2)

CACNB4-related disorder (1)

Episodic ataxia type 5 (1)

Idiopathic generalized epilepsy (1)

Juvenile myoclonic epilepsy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.087

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

PhyloP100

-0.21

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

REVEL

Benign

0.076

Sift

Uncertain

0.023

Sift4G

Benign

0.58

Polyphen

0.047

Vest4

0.16

MVP

0.76

MPC

0.66

ClinPred

0.016

GERP RS

-0.083

PromoterAI

-0.054

Neutral

(source)

Varity_R

0.067

gMVP

0.45

Mutation Taster

=97/3

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over