rs369438564
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_000719.7(CACNA1C):āc.5644T>Cā(p.Ser1882Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,613,636 control chromosomes in the GnomAD database, including 1 homozygotes. 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: š 0.00014 ( 1 hom., cov: 32)
Exomes š: 0.00017 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
4
12
Clinical Significance
Conservation
PhyloP100: 6.09
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=0.21634239).
BP6
?
Variant 12-2685806-T-C is Benign according to our data. Variant chr12-2685806-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS2
?
High AC in GnomAd4 at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5644T>C | p.Ser1882Pro | missense_variant | 44/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5644T>C | p.Ser1882Pro | missense_variant | 44/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.333+4334A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5644T>C | p.Ser1882Pro | missense_variant | 44/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5644T>C | p.Ser1882Pro | missense_variant | 44/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.294+4334A>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152130Hom.: 1 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000149 AC: 37AN: 248936Hom.: 0 AF XY: 0.000163 AC XY: 22AN XY: 135056
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GnomAD4 exome AF: 0.000170 AC: 248AN: 1461388Hom.: 0 Cov.: 31 AF XY: 0.000182 AC XY: 132AN XY: 726982
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GnomAD4 genome ? AF: 0.000145 AC: 22AN: 152248Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25633834) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 28, 2014 | - - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2022 | 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
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;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
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
Benign
T
PROVEAN
Uncertain
D;N;N;N;D;N;D;D;N;N;D;D;N;N;N;D;N;D;N;D;D;D;.
REVEL
Benign
Sift
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;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
0.0, 0.31, 0.18, 0.86, 0.88, 0.78, 1.0, 0.94, 0.93, 0.70, 0.87, 0.86, 0.98
.;B;B;B;B;P;P;P;B;D;P;P;P;P;P;.;P;P;.;.;.;D;.
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