12-2115383-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_000719.7(CACNA1C):āc.209A>Gā(p.Asn70Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,146 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 34)
Exomes š: 6.9e-7 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
2
6
7
Clinical Significance
Conservation
PhyloP100: 6.11
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 where missense usually causes diseases, CACNA1C
BP4
Computational evidence support a benign effect (MetaRNN=0.298137).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.209A>G | p.Asn70Ser | missense_variant | 2/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.209A>G | p.Asn70Ser | missense_variant | 2/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.209A>G | p.Asn70Ser | missense_variant | 2/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.209A>G | p.Asn70Ser | missense_variant | 2/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 34
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1456910Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 724650
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74368
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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 19, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 70 of the CACNA1C protein (p.Asn70Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 456951). 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. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
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;T
MetaSVM
Uncertain
D
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G
Pathogenic
D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.23, 0.0050, 0.022, 0.57, 0.024, 0.63
.;.;B;.;B;B;B;B;P;P;B;B;P;P;B;B;P;.;P;P;.;.;.;.
Vest4
0.44, 0.47, 0.45, 0.49, 0.49, 0.45, 0.48, 0.48, 0.49, 0.44, 0.45, 0.46, 0.48, 0.42, 0.49, 0.40, 0.51, 0.48, 0.44
MutPred
0.31
.;Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);
MVP
MPC
0.86
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