rs1008863902
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000719.7(CACNA1C):āc.5158C>Gā(p.Gln1720Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
2
9
5
Clinical Significance
Conservation
PhyloP100: 5.50
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CACNA1C
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5158C>G | p.Gln1720Glu | missense_variant | 42/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5158C>G | p.Gln1720Glu | missense_variant | 42/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.334-1613G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5158C>G | p.Gln1720Glu | missense_variant | 42/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5158C>G | p.Gln1720Glu | missense_variant | 42/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.295-1613G>C | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458790Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725306
GnomAD4 exome
AF:
AC:
3
AN:
1458790
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
725306
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
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 | Aug 31, 2021 | This sequence change replaces glutamine with glutamic acid at codon 1720 of the CACNA1C protein (p.Gln1720Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
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;.
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;D;D;D;T;T;T;T;D;T;D;T;D;T;D;D;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
0.98, 0.18, 0.85, 0.50, 0.99, 0.99, 0.72, 0.98, 0.97, 0.99, 0.92
.;D;B;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;P;.
Vest4
MutPred
0.34
.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at R1763 (P = 0.052);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
MPC
0.24
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