rs578106427
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_201596.3(CACNB2):c.1124C>T(p.Ala375Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,598 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A375T) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.1124C>T | p.Ala375Val | missense_variant | 11/14 | ENST00000324631.13 | |
CACNB2 | NM_201590.3 | c.962C>T | p.Ala321Val | missense_variant | 10/13 | ENST00000377329.10 | |
LOC124902387 | XR_007062077.1 | n.652G>A | non_coding_transcript_exon_variant | 1/2 | |||
LOC124902386 | XR_007062076.1 | n.83+5049G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.1124C>T | p.Ala375Val | missense_variant | 11/14 | 1 | NM_201596.3 | ||
CACNB2 | ENST00000377329.10 | c.962C>T | p.Ala321Val | missense_variant | 10/13 | 1 | NM_201590.3 | ||
ENST00000425669.1 | n.482+5049G>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251430Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135886
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461362Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 726964
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74430
ClinVar
Submissions by phenotype
Brugada syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 30, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 575601). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (rs578106427, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 321 of the CACNB2 protein (p.Ala321Val). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 18, 2023 | The p.A321V variant (also known as c.962C>T), located in coding exon 10 of the CACNB2 gene, results from a C to T substitution at nucleotide position 962. The alanine at codon 321 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at