rs550612732
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000399655.6(CACNA1C):c.4232+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000634 in 1,576,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000063 ( 0 hom. )
Consequence
CACNA1C
ENST00000399655.6 splice_donor_region, intron
ENST00000399655.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0003018
2
Clinical Significance
Conservation
PhyloP100: 1.49
Genes affected
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BS2
High AC in GnomAdExome4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.4232+4G>A | splice_donor_region_variant, intron_variant | ENST00000399655.6 | NP_000710.5 | |||
CACNA1C | NM_001167623.2 | c.4232+4G>A | splice_donor_region_variant, intron_variant | ENST00000399603.6 | NP_001161095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.4232+4G>A | splice_donor_region_variant, intron_variant | 5 | NM_001167623.2 | ENSP00000382512 | ||||
CACNA1C | ENST00000399655.6 | c.4232+4G>A | splice_donor_region_variant, intron_variant | 1 | NM_000719.7 | ENSP00000382563 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000809 AC: 2AN: 247066Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133938
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GnomAD4 exome AF: 0.00000632 AC: 9AN: 1423968Hom.: 0 Cov.: 25 AF XY: 0.00000704 AC XY: 5AN XY: 710468
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74400
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 30, 2018 | This sequence change falls in intron 34 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs550612732, ExAC 0.007%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 411738). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at