rs150528041
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_201596.3(CACNB2):c.590C>T(p.Ser197Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,613,852 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 0.00063 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 1 hom. )
Consequence
CACNB2
NM_201596.3 missense
NM_201596.3 missense
Scores
3
12
4
Clinical Significance
Conservation
PhyloP100: 6.17
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 -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18280962).
BP6
?
Variant 10-18500945-C-T is Benign according to our data. Variant chr10-18500945-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161210.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=1}. Variant chr10-18500945-C-T is described in Lovd as [Likely_benign].
BS2
?
High AC in GnomAd4 at 96 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.590C>T | p.Ser197Phe | missense_variant | 5/14 | ENST00000324631.13 | |
CACNB2 | NM_201590.3 | c.428C>T | p.Ser143Phe | missense_variant | 4/13 | ENST00000377329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.590C>T | p.Ser197Phe | missense_variant | 5/14 | 1 | NM_201596.3 | ||
CACNB2 | ENST00000377329.10 | c.428C>T | p.Ser143Phe | missense_variant | 4/13 | 1 | NM_201590.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000631 AC: 96AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000510 AC: 128AN: 251058Hom.: 1 AF XY: 0.000560 AC XY: 76AN XY: 135698
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GnomAD4 exome AF: 0.00108 AC: 1579AN: 1461568Hom.: 1 Cov.: 32 AF XY: 0.000993 AC XY: 722AN XY: 727090
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GnomAD4 genome ? AF: 0.000630 AC: 96AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32AN XY: 74458
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:10
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CACNB2: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2019 | This variant is associated with the following publications: (PMID: 26707467, 20817017, 31887354, 24055113, 23414114, 25637381, 24752249, 27711072, 25467552, 30821013, 30847666) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 18, 2018 | Variant summary: CACNB2 c.428C>T (p.Ser143Phe) results in a non-conservative amino acid change located in the Guanylate kinase/L-type calcium channel beta subunit of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 278284 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 352 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Brugada Syndrome phenotype (3.1e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.428C>T has been reported in the literature in individuals affected with Brugada Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. In addition, there was no statistical difference in mean J-point elevation between carriers and non-carriers (Ghouse_2017), also supporting a benign outcome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely benign and 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only associated with autism; ExAC: 0.1% (60/65764) European chromosomes - |
Brugada syndrome 4 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2021 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Feb 26, 2019 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;T;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;.;D;.;D;D;D;.;D;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;.;D;.;D;D;D;.;D;.;.
Sift4G
Uncertain
D;D;.;.;D;D;D;D;D;D;D;.;.
Polyphen
P;P;.;.;P;.;.;D;P;P;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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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