rs143326262
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_201596.3(CACNB2):c.1511C>T(p.Thr504Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,042 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_201596.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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CACNB2 | ENST00000324631.13 | c.1511C>T | p.Thr504Ile | missense_variant | Exon 14 of 14 | 1 | NM_201596.3 | ENSP00000320025.8 | ||
CACNB2 | ENST00000377329.10 | c.1349C>T | p.Thr450Ile | missense_variant | Exon 13 of 13 | 1 | NM_201590.3 | ENSP00000366546.4 |
Frequencies
GnomAD3 genomes AF: 0.00166 AC: 253AN: 152078Hom.: 2 Cov.: 31
GnomAD3 exomes AF: 0.00148 AC: 373AN: 251302Hom.: 0 AF XY: 0.00153 AC XY: 208AN XY: 135838
GnomAD4 exome AF: 0.00288 AC: 4214AN: 1461846Hom.: 11 Cov.: 31 AF XY: 0.00278 AC XY: 2022AN XY: 727230
GnomAD4 genome AF: 0.00166 AC: 253AN: 152196Hom.: 2 Cov.: 31 AF XY: 0.00142 AC XY: 106AN XY: 74418
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:3
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Variant summary: The CACNB2 c.1349C>T (p.Thr450Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 449/289284 control chromosomes (1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00279 (353/126520). This frequency is about 893 times the estimated maximal expected allele frequency of a pathogenic CACNB2 variant (0.0000031), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Though this variant has been reported in 2 individuals in a single family with BrS in an early study (Burashnikov 2010), later population studies indicated that the variant is not associated with BrS specific ECG patterns (Risgaard 2013, Ghouse 2017) and one study reports non-segregation of the variant with disease in a family (Allegue_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign. -
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 1 proband in HGMD, ExAC: 0.2% (159/66588) European chromosomes -
not provided Benign:3Other:1
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See Variant Classification Assertion Criteria. -
Variant classified as Uncertain significance and reported on 11-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
CACNB2: BP4, BS2; ENSG00000240291: BS2 -
Brugada syndrome 4 Benign:2
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Brugada syndrome Uncertain:1
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Long QT syndrome Benign:1
Criteria: BS1, BS2 -
CACNB2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
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. -
Ventricular tachycardia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at