rs373263114
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_201596.3(CACNB2):c.104T>C(p.Leu35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,602,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
CACNB2
NM_201596.3 missense
NM_201596.3 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 0.341
Genes affected
CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.03967476).
BS2
?
High AC in GnomAd at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.104T>C | p.Leu35Pro | missense_variant | 1/14 | ENST00000324631.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.104T>C | p.Leu35Pro | missense_variant | 1/14 | 1 | NM_201596.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000645 AC: 14AN: 216944Hom.: 0 AF XY: 0.0000503 AC XY: 6AN XY: 119330
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GnomAD4 exome AF: 0.000113 AC: 164AN: 1450050Hom.: 1 Cov.: 32 AF XY: 0.000106 AC XY: 76AN XY: 720206
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brugada syndrome 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 04, 2020 | The CACNB2 c.104T>C, p.Leu35Pro variant (also annotated as NM_201590.2(CACNB2):c.-200087T>C; rs373263114), has been previously observed in a family with primary electrical disease (arrhythmia without structural defects); however, it did not segregate with all effected family members (Proost 2017). This variant is also found in the general population with an overall allele frequency of 0.006% (15/248,332 alleles) in the Genome Aggregation Database and is listed in ClinVar (Variation ID: 191429). The leucine at codon 35 is weakly conserved (Alamut v.2.11) and computational analyses predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain. References: Proost D et al. Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn. 2017 May;19(3):445-459. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 23, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2021 | Reported in a patient with primary electrical disease, defined as cardiac arrhythmia in the absence of structural heart disease, but was also identified in the control cohort (Proost et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 28341588) - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;T
Sift4G
Benign
T;T;T
Polyphen
P;B;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at