dbSNP rs369342902: CACNB4:c.64-238T>G (chr2-152098651-A-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001005746.4(CACNB4):c.-2T>G variant causes a 5 prime UTR 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_001005746.4 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.86

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:

ENSG00000225214 (HGNC:):

ENSG00000225214 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 446970.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB4	NM_000726.5 link	c.64-238T>G		intron_variant	Intron 1 of 13	ENST00000539935.7	NP_000717.2	O00305-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB4	ENST00000539935.7 link	c.64-238T>G		intron_variant	Intron 1 of 13	1	NM_000726.5	ENSP00000438949.1		O00305-1

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

GnomAD3 exomes

AF:

0.000225

AC:

AN:

186476

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

100468

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 SAS 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

Gnomad4 AFR exome

AF:

0.000124

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00111

Gnomad4 OTH exome

AF:

0.00165

GnomAD4 genome

AF:

0.000409

AC:

AN:

151724

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000811

Gnomad4 OTH

AF:

0.00

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.90

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