rs768976112
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000726.5(CACNB4):c.147+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CACNB4
NM_000726.5 splice_donor_region, intron
NM_000726.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9970
2
Clinical Significance
Conservation
PhyloP100: 1.82
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB4 | NM_000726.5 | c.147+3A>G | splice_donor_region_variant, intron_variant | ENST00000539935.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB4 | ENST00000539935.7 | c.147+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_000726.5 | ||||
ENST00000420365.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248592Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134914
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459550Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726202
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Idiopathic generalized epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2017 | This variant has not been reported in the literature in individuals with CACNB4-related disease. This variant is present in population databases (rs768976112, ExAC 0.002%). This sequence change falls in intron 2 of the CACNB4 gene. It does not directly change the encoded amino acid sequence of the CACNB4 protein, but it affects a nucleotide within the consensus splice site of the intron. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
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Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
Find out detailed SpliceAI scores and Pangolin per-transcript scores at