chr3-50374819-G-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000424201.7(CACNA2D2):c.1908-6C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000946 in 1,585,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000084 ( 0 hom. )
Consequence
CACNA2D2
ENST00000424201.7 splice_region, splice_polypyrimidine_tract, intron
ENST00000424201.7 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.03807
2
Clinical Significance
Conservation
PhyloP100: 0.810
Genes affected
CACNA2D2 (HGNC:1400): (calcium voltage-gated channel auxiliary subunit alpha2delta 2) Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA2D2 | NM_006030.4 | c.1908-6C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000424201.7 | NP_006021.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA2D2 | ENST00000424201.7 | c.1908-6C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_006030.4 | ENSP00000390329 | P4 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152002Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000495 AC: 1AN: 202180Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 108696
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GnomAD4 exome AF: 0.00000837 AC: 12AN: 1433854Hom.: 0 Cov.: 32 AF XY: 0.00000563 AC XY: 4AN XY: 710498
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GnomAD4 genome 0.0000197 AC: 3AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74244
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 08, 2022 | This sequence change falls in intron 21 of the CACNA2D2 gene. It does not directly change the encoded amino acid sequence of the CACNA2D2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -33
Find out detailed SpliceAI scores and Pangolin per-transcript scores at