rs200092211
Positions:
Variant summary
Our verdict is Benign. Variant got -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
NM_000726.5 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 2.67
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -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 id is 193120.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=4, Likely_benign=2}. Variant chr2-152099007-G-A is described in Lovd as [Likely_benign].
BS2
?
High AC in GnomAd4 at 138 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB4 | NM_000726.5 | c.5C>T | p.Ser2Phe | missense_variant | 1/14 | ENST00000539935.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB4 | ENST00000539935.7 | c.5C>T | p.Ser2Phe | missense_variant | 1/14 | 1 | NM_000726.5 | ||
ENST00000420365.1 | n.120+560G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000907 AC: 138AN: 152112Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00145 AC: 195AN: 134704Hom.: 0 AF XY: 0.00121 AC XY: 88AN XY: 72796
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GnomAD4 exome AF: 0.000873 AC: 1206AN: 1381012Hom.: 1 Cov.: 31 AF XY: 0.000889 AC XY: 606AN XY: 681524
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GnomAD4 genome ? AF: 0.000907 AC: 138AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71AN XY: 74426
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2017 | The S2F variant of unknown significance has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The 1000 Genomes Project reports S2F was observed in 1/214 alleles (0.5%) from individuals of Italian background (McVean et al., 2012). The S2F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position in the N-terminal region of the CACNB4 protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to date only a small number of substitutions in CACNB4 have been published in association with epilepsy, and no pathogenic variants have been reported in the N-terminal region of the protein (Escayg et al., 2000; Ohmori et al., 2008). Therefore, based on the currently available information, it is unclear whether S2F is a pathogenic or a rare benign variant. - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | CACNB4: BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 04, 2015 | - - |
Epilepsy, idiopathic generalized, susceptibility to, 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 31, 2016 | - - |
Episodic ataxia type 5;C2750887:Epilepsy, idiopathic generalized, susceptibility to, 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Juvenile myoclonic epilepsy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
CACNB4-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 26, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Episodic ataxia type 5 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Idiopathic generalized epilepsy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;L
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N
REVEL
Uncertain
Sift
Pathogenic
D;.;.;D
Sift4G
Uncertain
D;.;.;D
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at