Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000726.5(CACNB4):c.311G>T(p.Cys104Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000876 in 1,613,588 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C104Y) has been classified as Uncertain significance.
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]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.15203032).
BP6
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BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-151880879-C-A is Benign according to our data. Variant chr2-151880879-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7608.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Uncertain significance, no assertion criteria provided
clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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- -
Uncertain significance, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht
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- -
Uncertain significance, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Benign, criteria provided, single submitter
clinical testing
GeneDx
Jan 16, 2019
This variant is associated with the following publications: (PMID: 10762541) -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Nov 01, 2023
CACNB4: PP3, BS1 -
Episodic ataxia type 5 Pathogenic:1Benign:1
Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Mar 06, 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. -
Pathogenic, no assertion criteria provided
literature only
OMIM
May 01, 2000
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Juvenile myoclonic epilepsy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jun 14, 2016
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CACNB4-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Apr 26, 2023
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). -
Idiopathic generalized epilepsy Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Sep 25, 2023
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Epilepsy, idiopathic generalized, susceptibility to, 9 Other:1