rs753954220
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_000719.7(CACNA1C):c.5684G>A(p.Arg1895Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
4
5
7
Clinical Significance
Conservation
PhyloP100: 9.26
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 -4 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, CACNA1C
BP6
?
Variant 12-2686169-G-A is Benign according to our data. Variant chr12-2686169-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526961.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
?
High AC in GnomAdExome4 at 40 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5684G>A | p.Arg1895Gln | missense_variant | 45/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5684G>A | p.Arg1895Gln | missense_variant | 45/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.333+3971C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5684G>A | p.Arg1895Gln | missense_variant | 45/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5684G>A | p.Arg1895Gln | missense_variant | 45/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.294+3971C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249302Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135248
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461462Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727048
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 11, 2021 | - - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2024 | 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
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
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
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Benign
Sift
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;T;D;D;D;T;T;D;D;D;T;D;D
Polyphen
1.0, 0.43, 0.99, 0.98, 1.0, 0.16
.;D;B;D;D;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4
MVP
MPC
0.24
ClinPred
D
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