10-18538309-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_201596.3(CACNB2):c.1432C>T(p.Arg478Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R478G) has been classified as Uncertain significance.
Frequency
Consequence
NM_201596.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.1432C>T | p.Arg478Cys | missense_variant | 13/14 | ENST00000324631.13 | |
CACNB2 | NM_201590.3 | c.1270C>T | p.Arg424Cys | missense_variant | 12/13 | ENST00000377329.10 | |
LOC124902386 | XR_007062076.1 | n.83+885G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.1432C>T | p.Arg478Cys | missense_variant | 13/14 | 1 | NM_201596.3 | ||
CACNB2 | ENST00000377329.10 | c.1270C>T | p.Arg424Cys | missense_variant | 12/13 | 1 | NM_201590.3 | ||
ENST00000425669.1 | n.482+885G>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251468Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135902
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727234
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Brugada syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 12, 2021 | This sequence change replaces arginine with cysteine at codon 424 of the CACNB2 protein (p.Arg424Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216845). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2022 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at