rs200330326
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000719.7(CACNA1C):c.4944G>A(p.Ala1648Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,510 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000035 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 synonymous
NM_000719.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.34
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 12-2677209-G-A is Benign according to our data. Variant chr12-2677209-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000184 (28/152322) while in subpopulation AFR AF= 0.000649 (27/41592). AF 95% confidence interval is 0.000458. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 28 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1C | NM_000719.7 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | ENST00000399655.6 | NP_000710.5 | |
| CACNA1C | NM_001167623.2 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1C | ENST00000399603.6 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
| CACNA1C | ENST00000399655.6 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
| CACNA1C | ENST00000682544.1 | c.5178G>A | p.Ala1726Ala | synonymous_variant | 42/50 | ENSP00000507184.1 | ||||
| CACNA1C | ENST00000406454.8 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/48 | 5 | ENSP00000385896.3 | |||
| CACNA1C | ENST00000399634.6 | c.4911G>A | p.Ala1637Ala | synonymous_variant | 39/47 | 5 | ENSP00000382542.2 | |||
| CACNA1C | ENST00000683824.1 | c.5109G>A | p.Ala1703Ala | synonymous_variant | 41/48 | ENSP00000507867.1 | ||||
| CACNA1C | ENST00000347598.9 | c.5088G>A | p.Ala1696Ala | synonymous_variant | 42/49 | 1 | ENSP00000266376.6 | |||
| CACNA1C | ENST00000344100.7 | c.5067G>A | p.Ala1689Ala | synonymous_variant | 40/47 | 1 | ENSP00000341092.3 | |||
| CACNA1C | ENST00000327702.12 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/48 | 1 | ENSP00000329877.7 | |||
| CACNA1C | ENST00000399617.6 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/48 | 5 | ENSP00000382526.1 | |||
| CACNA1C | ENST00000682462.1 | c.5034G>A | p.Ala1678Ala | synonymous_variant | 40/47 | ENSP00000507105.1 | ||||
| CACNA1C | ENST00000683781.1 | c.5034G>A | p.Ala1678Ala | synonymous_variant | 40/47 | ENSP00000507434.1 | ||||
| CACNA1C | ENST00000683840.1 | c.5034G>A | p.Ala1678Ala | synonymous_variant | 40/47 | ENSP00000507612.1 | ||||
| CACNA1C | ENST00000683956.1 | c.5034G>A | p.Ala1678Ala | synonymous_variant | 40/47 | ENSP00000506882.1 | ||||
| CACNA1C | ENST00000399638.5 | c.5028G>A | p.Ala1676Ala | synonymous_variant | 41/48 | 1 | ENSP00000382547.1 | |||
| CACNA1C | ENST00000335762.10 | c.5019G>A | p.Ala1673Ala | synonymous_variant | 41/48 | 5 | ENSP00000336982.5 | |||
| CACNA1C | ENST00000399606.5 | c.5004G>A | p.Ala1668Ala | synonymous_variant | 41/48 | 1 | ENSP00000382515.1 | |||
| CACNA1C | ENST00000399621.5 | c.5001G>A | p.Ala1667Ala | synonymous_variant | 40/47 | 1 | ENSP00000382530.1 | |||
| CACNA1C | ENST00000399637.5 | c.5001G>A | p.Ala1667Ala | synonymous_variant | 40/47 | 1 | ENSP00000382546.1 | |||
| CACNA1C | ENST00000402845.7 | c.5001G>A | p.Ala1667Ala | synonymous_variant | 40/47 | 1 | ENSP00000385724.3 | |||
| CACNA1C | ENST00000399629.5 | c.4995G>A | p.Ala1665Ala | synonymous_variant | 40/47 | 1 | ENSP00000382537.1 | |||
| CACNA1C | ENST00000682336.1 | c.4986G>A | p.Ala1662Ala | synonymous_variant | 40/47 | ENSP00000507898.1 | ||||
| CACNA1C | ENST00000399591.5 | c.4968G>A | p.Ala1656Ala | synonymous_variant | 39/46 | 1 | ENSP00000382500.1 | |||
| CACNA1C | ENST00000399595.5 | c.4968G>A | p.Ala1656Ala | synonymous_variant | 39/46 | 1 | ENSP00000382504.1 | |||
| CACNA1C | ENST00000399649.5 | c.4962G>A | p.Ala1654Ala | synonymous_variant | 39/46 | 1 | ENSP00000382557.1 | |||
| CACNA1C | ENST00000399597.5 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | 1 | ENSP00000382506.1 | |||
| CACNA1C | ENST00000399601.5 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | 1 | ENSP00000382510.1 | |||
| CACNA1C | ENST00000399641.6 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | 1 | ENSP00000382549.1 | |||
| CACNA1C | ENST00000399644.5 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | 1 | ENSP00000382552.1 | |||
| CACNA1C | ENST00000682835.1 | c.4944G>A | p.Ala1648Ala | synonymous_variant | 40/47 | ENSP00000507282.1 | ||||
| CACNA1C | ENST00000683482.1 | c.4935G>A | p.Ala1645Ala | synonymous_variant | 40/47 | ENSP00000507169.1 | ||||
| CACNA1C | ENST00000682686.1 | c.4911G>A | p.Ala1637Ala | synonymous_variant | 39/46 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes 0.000151 AC: 23AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000282 AC: 7AN: 247936Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134592
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GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461188Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 726832
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GnomAD4 genome 0.000184 AC: 28AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20AN XY: 74478
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ClinVar
Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CACNA1C-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 22, 2020 | 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). - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2020 | - - |
Long QT syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2018 | 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
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at