rs200092211

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

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=0.016155422).

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 VariationId is 193120.

BS2

High AC in GnomAd4 at 138 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.5C>T	p.Ser2Phe	missense	Exon 1 of 14	NP_000717.2	O00305-1
CACNB4	NM_001145798.2		c.5C>T	p.Ser2Phe	missense	Exon 1 of 13	NP_001139270.1	O00305-4
CACNB4	NM_001005746.4		c.-358C>T		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.5C>T	p.Ser2Phe	missense	Exon 1 of 14	ENSP00000438949.1	O00305-1
CACNB4	ENST00000201943.10	TSL:1	c.5C>T	p.Ser2Phe	missense	Exon 1 of 13	ENSP00000201943.5	O00305-4
CACNB4	ENST00000427385.6	TSL:5	c.5C>T	p.Ser2Phe	missense	Exon 1 of 13	ENSP00000410978.2	A0A1C7CYX2

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

GnomAD2 exomes

AF:

0.00145

AC:

195

AN:

134704

AF XY:

0.00121

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 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

African (AFR)

AF:

0.000133

AC:

AN:

30108

American (AMR)

AF:

0.00176

AC:

AN:

30136

Ashkenazi Jewish (ASJ)

AF:

0.0100

AC:

242

AN:

24182

East Asian (EAS)

AF:

0.00

AC:

AN:

34380

South Asian (SAS)

AF:

0.000299

AC:

AN:

76952

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

49078

Middle Eastern (MID)

AF:

0.00285

AC:

AN:

4562

European-Non Finnish (NFE)

AF:

0.000732

AC:

787

AN:

1074524

Other (OTH)

AF:

0.00145

AC:

AN:

57090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000907

AC:

138

AN:

152230

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41566

American (AMR)

AF:

0.00209

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00119

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000728

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

CACNB4-related disorder (1)

Epilepsy, idiopathic generalized, susceptibility to, 9 (1)

Episodic ataxia type 5 (1)

Episodic ataxia type 5;C2750887:Epilepsy, idiopathic generalized, susceptibility to, 9 (1)

Idiopathic generalized epilepsy (1)

Juvenile myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.81

PhyloP100

2.7

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.61

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.97

Vest4

0.47

MVP

0.87

MPC

1.7

ClinPred

0.18

GERP RS

2.7

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.22

gMVP

0.43

Mutation Taster

=80/20

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