12-2593315-G-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_000719.7(CACNA1C):c.2633G>C(p.Ser878Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S878I) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
1
6
10
Clinical Significance
Conservation
PhyloP100: 5.67
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
BP4
Computational evidence support a benign effect (MetaRNN=0.34492218).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.2633G>C | p.Ser878Thr | missense_variant | 19/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.2633G>C | p.Ser878Thr | missense_variant | 19/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.2633G>C | p.Ser878Thr | missense_variant | 19/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.2633G>C | p.Ser878Thr | missense_variant | 19/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
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 | Sep 20, 2016 | This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1C-related disease. This sequence change replaces serine with threonine at codon 878 of the CACNA1C protein (p.Ser878Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
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
Pathogenic
D
MutationAssessor
Benign
.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
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
0.0010, 0.0, 0.10, 0.0090, 0.21, 0.0020, 0.99, 0.0050, 0.0080
.;B;B;B;B;B;B;B;B;B;B;B;B;B;D;B;.;B;B;.;B;.;B
Vest4
MutPred
0.40
.;Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);
MVP
MPC
1.7
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at