rs369342902

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000726.5(CACNB4):c.64-238T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000872 in 1,572,784 control chromosomes in the GnomAD database, including 2 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 0.00041 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00092 ( 2 hom. )

Consequence

CACNB4
NM_000726.5 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.86

Publications

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

CACNB4 links:

ENSG00000299271 (HGNC:):

ENSG00000299271 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 2-152098651-A-C is Benign according to our data. Variant chr2-152098651-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446970.

BS2

High AC in GnomAd4 at 62 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	Effect	Exon Rank	Protein
CACNB4	NM_000726.5	MANE Select	c.64-238T>G	intron	N/A	NP_000717.2
CACNB4	NM_001005746.4		c.-2T>G	5_prime_UTR	Exon 1 of 14	NP_001005746.1
CACNB4	NM_001330113.2		c.-2T>G	5_prime_UTR	Exon 1 of 11	NP_001317042.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CACNB4	ENST00000539935.7	TSL:1 MANE Select	c.64-238T>G	intron	N/A	ENSP00000438949.1
CACNB4	ENST00000201943.10	TSL:1	c.64-238T>G	intron	N/A	ENSP00000201943.5
CACNB4	ENST00000636762.1	TSL:5	n.-2T>G	non_coding_transcript_exon	Exon 1 of 14	ENSP00000490918.1

Frequencies

GnomAD3 genomes

AF:

0.000409

AC:

AN:

151602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000811

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000225

AC:

AN:

186476

AF XY:

0.000239

show subpopulations

Gnomad AFR exome

AF:

0.000102

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000507

Gnomad OTH exome

AF:

0.000202

GnomAD4 exome

AF:

0.000921

AC:

1309

AN:

1421060

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

605

AN XY:

703026

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

32358

American (AMR)

AF:

0.00

AC:

AN:

39278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25436

East Asian (EAS)

AF:

0.00

AC:

AN:

37132

South Asian (SAS)

AF:

0.00

AC:

AN:

80652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00111

AC:

1208

AN:

1091412

Other (OTH)

AF:

0.00165

AC:

AN:

58922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.000409

AC:

AN:

151724

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000811

AC:

AN:

67834

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000622

Hom.:

Bravo

AF:

0.000419

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

May 11, 2021

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNB4-related disorder

Benign:1

Jul 06, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

2.9

PromoterAI

-0.032

Neutral

(source)

Mutation Taster

=299/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over