rs1555193020
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_000719.7(CACNA1C):c.232T>A(p.Ser78Thr) 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 (★). Synonymous variant affecting the same amino acid position (i.e. S78S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
5
11
Clinical Significance
Conservation
PhyloP100: 4.98
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]
Genome browser will be placed here
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 where missense usually causes diseases, CACNA1C
BP4
?
Computational evidence support a benign effect (MetaRNN=0.31290662).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.232T>A | p.Ser78Thr | missense_variant | 2/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.232T>A | p.Ser78Thr | missense_variant | 2/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.232T>A | p.Ser78Thr | missense_variant | 2/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.232T>A | p.Ser78Thr | missense_variant | 2/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
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 | Invitae | Jul 29, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with threonine at codon 78 of the CACNA1C protein (p.Ser78Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
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;D;D;D
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;N
REVEL
Benign
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
0.95, 0.11, 0.85, 0.97, 0.98, 0.049, 0.99, 0.99
.;P;.;B;P;D;P;D;D;B;P;D;D;P;P;D;.;D;D;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);Gain of catalytic residue at S77 (P = 2e-04);
MVP
MPC
1.0
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