rs751029383
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000726.5(CACNB4):āc.988A>Gā(p.Ile330Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,547,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000018 ( 0 hom. )
Consequence
CACNB4
NM_000726.5 missense
NM_000726.5 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 8.02
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAdExome4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB4 | NM_000726.5 | c.988A>G | p.Ile330Val | missense_variant | 11/14 | ENST00000539935.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB4 | ENST00000539935.7 | c.988A>G | p.Ile330Val | missense_variant | 11/14 | 1 | NM_000726.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246976Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133988
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GnomAD4 exome AF: 0.0000179 AC: 25AN: 1395706Hom.: 0 Cov.: 29 AF XY: 0.0000203 AC XY: 14AN XY: 688064
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
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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 | Mar 19, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 575863). This variant has not been reported in the literature in individuals affected with CACNB4-related conditions. This variant is present in population databases (rs751029383, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 330 of the CACNB4 protein (p.Ile330Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;T;T;T;T;T;.;T;T;T;.;.;.;T;T;.;.;.;.;T;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;N;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;D;.
Sift4G
Uncertain
T;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;D;.
Polyphen
P;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at