rs781306162
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2
The NM_000719.7(CACNA1C):āc.1649A>Gā(p.Asn550Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000388 in 1,598,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000041 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
1
2
13
Clinical Significance
Conservation
PhyloP100: 4.25
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 Benign. Variant got -13 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, CACNA1C
BP4
?
Computational evidence support a benign effect (MetaRNN=0.1659621).
BP6
?
Variant 12-2566562-A-G is Benign according to our data. Variant chr12-2566562-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 575658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High AC in GnomAdExome4 at 59 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.1649A>G | p.Asn550Ser | missense_variant | 12/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.1649A>G | p.Asn550Ser | missense_variant | 12/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.1649A>G | p.Asn550Ser | missense_variant | 12/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.1649A>G | p.Asn550Ser | missense_variant | 12/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000178 AC: 4AN: 224750Hom.: 0 AF XY: 0.0000165 AC XY: 2AN XY: 121332
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GnomAD4 exome AF: 0.0000408 AC: 59AN: 1446438Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 29AN XY: 717842
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74348
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 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
Benign
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
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
MetaSVM
Uncertain
T
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
Benign
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
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
0.0, 0.0010, 0.018
.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B
Vest4
MutPred
0.35
.;Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);
MVP
MPC
0.85
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