rs200602896
Positions:
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_000719.7(CACNA1C):c.618G>A(p.Gly206Gly) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000633 in 1,610,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 splice_region, synonymous
NM_000719.7 splice_region, synonymous
Scores
2
Splicing: ADA: 0.7660
2
Clinical Significance
Conservation
PhyloP100: 6.84
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 -18 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.26).
BP6
Variant 12-2457567-G-A is Benign according to our data. Variant chr12-2457567-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00023 (35/152192) while in subpopulation AMR AF= 0.00164 (25/15282). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 35 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1C | NM_000719.7 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | ENST00000399655.6 | NP_000710.5 | |
| CACNA1C | NM_001167623.2 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1C | ENST00000399603.6 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
| CACNA1C | ENST00000399655.6 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
| CACNA1C | ENST00000682544.1 | c.708G>A | p.Gly236Gly | splice_region_variant, synonymous_variant | 5/50 | ENSP00000507184.1 | ||||
| CACNA1C | ENST00000406454.8 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/48 | 5 | ENSP00000385896.3 | |||
| CACNA1C | ENST00000399634.6 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 5 | ENSP00000382542.2 | |||
| CACNA1C | ENST00000683824.1 | c.708G>A | p.Gly236Gly | splice_region_variant, synonymous_variant | 5/48 | ENSP00000507867.1 | ||||
| CACNA1C | ENST00000347598.9 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/49 | 1 | ENSP00000266376.6 | |||
| CACNA1C | ENST00000344100.7 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000341092.3 | |||
| CACNA1C | ENST00000327702.12 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/48 | 1 | ENSP00000329877.7 | |||
| CACNA1C | ENST00000399617.6 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/48 | 5 | ENSP00000382526.1 | |||
| CACNA1C | ENST00000682462.1 | c.708G>A | p.Gly236Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000507105.1 | ||||
| CACNA1C | ENST00000683781.1 | c.708G>A | p.Gly236Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000507434.1 | ||||
| CACNA1C | ENST00000683840.1 | c.708G>A | p.Gly236Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000507612.1 | ||||
| CACNA1C | ENST00000683956.1 | c.708G>A | p.Gly236Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000506882.1 | ||||
| CACNA1C | ENST00000399638.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/48 | 1 | ENSP00000382547.1 | |||
| CACNA1C | ENST00000335762.10 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/48 | 5 | ENSP00000336982.5 | |||
| CACNA1C | ENST00000399606.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/48 | 1 | ENSP00000382515.1 | |||
| CACNA1C | ENST00000399621.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382530.1 | |||
| CACNA1C | ENST00000399637.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382546.1 | |||
| CACNA1C | ENST00000402845.7 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000385724.3 | |||
| CACNA1C | ENST00000399629.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382537.1 | |||
| CACNA1C | ENST00000682336.1 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000507898.1 | ||||
| CACNA1C | ENST00000399591.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/46 | 1 | ENSP00000382500.1 | |||
| CACNA1C | ENST00000399595.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/46 | 1 | ENSP00000382504.1 | |||
| CACNA1C | ENST00000399649.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/46 | 1 | ENSP00000382557.1 | |||
| CACNA1C | ENST00000399597.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382506.1 | |||
| CACNA1C | ENST00000399601.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382510.1 | |||
| CACNA1C | ENST00000399641.6 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382549.1 | |||
| CACNA1C | ENST00000399644.5 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | 1 | ENSP00000382552.1 | |||
| CACNA1C | ENST00000682835.1 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000507282.1 | ||||
| CACNA1C | ENST00000683482.1 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/47 | ENSP00000507169.1 | ||||
| CACNA1C | ENST00000682686.1 | c.618G>A | p.Gly206Gly | splice_region_variant, synonymous_variant | 5/46 | ENSP00000507309.1 | ||||
| CACNA1C | ENST00000682152.1 | c.567G>A | p.Gly189Gly | splice_region_variant, synonymous_variant | 4/6 | ENSP00000506759.1 | ||||
| CACNA1C | ENST00000480911.6 | n.618G>A | splice_region_variant, non_coding_transcript_exon_variant | 5/27 | 5 | ENSP00000437936.2 |
Frequencies
GnomAD3 genomes 0.000230 AC: 35AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000893 AC: 22AN: 246334Hom.: 0 AF XY: 0.000112 AC XY: 15AN XY: 133754
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GnomAD4 exome AF: 0.0000459 AC: 67AN: 1458608Hom.: 0 Cov.: 30 AF XY: 0.0000551 AC XY: 40AN XY: 725518
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GnomAD4 genome 0.000230 AC: 35AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27AN XY: 74350
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 24, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2022 | Variant summary: CACNA1C c.618G>A (p.Gly206Gly) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.9e-05 in 246334 control chromosomes (gnomAD), predominantly at a frequency of 0.00051 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 51 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing the Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.618G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | CACNA1C: BP4 - |
| Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
CACNA1C-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 24, 2022 | 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). - |
Long QT syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
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