rs61733967
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_201596.3(CACNB2):c.1785C>T(p.His595=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,866 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0081 ( 19 hom., cov: 30)
Exomes 𝑓: 0.00077 ( 10 hom. )
Consequence
CACNB2
NM_201596.3 synonymous
NM_201596.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.71
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 -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
Variant 10-18539526-C-T is Benign according to our data. Variant chr10-18539526-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18539526-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-1.71 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1226/152022) while in subpopulation AFR AF= 0.0283 (1172/41448). AF 95% confidence interval is 0.0269. There are 19 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
?
High AC in GnomAd at 1222 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.1785C>T | p.His595= | synonymous_variant | 14/14 | ENST00000324631.13 | |
CACNB2 | NM_201590.3 | c.1623C>T | p.His541= | synonymous_variant | 13/13 | ENST00000377329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.1785C>T | p.His595= | synonymous_variant | 14/14 | 1 | NM_201596.3 | ||
CACNB2 | ENST00000377329.10 | c.1623C>T | p.His541= | synonymous_variant | 13/13 | 1 | NM_201590.3 | ||
ENST00000425669.1 | n.377-227G>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00804 AC: 1222AN: 151904Hom.: 19 Cov.: 30
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GnomAD3 exomes AF: 0.00206 AC: 518AN: 251280Hom.: 5 AF XY: 0.00144 AC XY: 195AN XY: 135810
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GnomAD4 exome AF: 0.000773 AC: 1130AN: 1461844Hom.: 10 Cov.: 35 AF XY: 0.000670 AC XY: 487AN XY: 727224
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brugada syndrome 4 Benign:3
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Aug 24, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2022 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2016 | Variant summary: The c.1623C>T variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 5/5 in silico tools via Alamut predict no significant effect on splicing. This variant is found in 317/121328 control chromosomes (5 homozygotes) at a frequency of 0.0026128, which is about 261 times of maximal expected frequency of a pathogenic allele (0.00001), suggesting this variant is benign. In addition, one clinical laboratory classified this variant as benign. The variant of interest has been found in one individual with co-occurrence of KCNQ1 c.674C>T/p.S225L (pathogenic) in our laboratory. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/other clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as benign. - |
CACNB2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 03, 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). - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2015 | This alteration is classified as 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
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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