rs200231105
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_000719.7(CACNA1C):c.5593G>A(p.Glu1865Lys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
1
3
13
Clinical Significance
Conservation
PhyloP100: 7.58
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.
PP2
?
Missense variant where missense usually causes diseases, CACNA1C
BP4
?
Computational evidence support a benign effect (MetaRNN=0.10103333).
BP6
?
Variant 12-2685755-G-A is Benign according to our data. Variant chr12-2685755-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191566.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=2}. Variant chr12-2685755-G-A is described in Lovd as [Benign].
BS2
?
High AC in GnomAdExome at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5593G>A | p.Glu1865Lys | missense_variant | 44/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5593G>A | p.Glu1865Lys | missense_variant | 44/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.333+4385C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5593G>A | p.Glu1865Lys | missense_variant | 44/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5593G>A | p.Glu1865Lys | missense_variant | 44/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.294+4385C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 271AN: 133776Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 genomes
?
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271
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133776
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32
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GnomAD3 exomes AF: 0.000117 AC: 29AN: 247782Hom.: 0 AF XY: 0.0000892 AC XY: 12AN XY: 134560
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000810 AC: 118AN: 1456592Hom.: 1 Cov.: 31 AF XY: 0.0000801 AC XY: 58AN XY: 724542
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00202 AC: 271AN: 133890Hom.: 0 Cov.: 32 AF XY: 0.00204 AC XY: 134AN XY: 65650
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | CACNA1C: BP4 - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1865 of the CACNA1C protein (p.Glu1865Lys). 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 missense change has been observed in individual(s) with clinical features of CACNA1C-related conditions (PMID: 32145446). This variant is also known as c.5617G>A (p.E1873K). ClinVar contains an entry for this variant (Variation ID: 191566). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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. - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Dec 24, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 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
Source:
Name
Calibrated prediction
Score
Prediction
CardioboostArm
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Benign
Sift
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T;T;D;T;D;.
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.94, 0.062, 0.33, 0.11, 0.95, 0.96, 0.59, 0.43, 0.98, 0.88, 1.0, 0.92, 0.76
.;P;B;B;B;P;D;D;P;P;B;D;P;D;D;.;D;P;.;.;.;P;.
Vest4
MVP
MPC
0.24
ClinPred
T
GERP RS
gMVP
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