rs751493277
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_000719.7(CACNA1C):āc.5164T>Gā(p.Phe1722Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,611,764 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: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
3
8
5
Clinical Significance
Conservation
PhyloP100: 5.46
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 12-2679516-T-G is Benign according to our data. Variant chr12-2679516-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526947.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
?
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5164T>G | p.Phe1722Val | missense_variant | 42/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5164T>G | p.Phe1722Val | missense_variant | 42/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.334-1619A>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5164T>G | p.Phe1722Val | missense_variant | 42/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5164T>G | p.Phe1722Val | missense_variant | 42/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.295-1619A>C | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000285 AC: 7AN: 245250Hom.: 0 AF XY: 0.0000375 AC XY: 5AN XY: 133314
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459678Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 725918
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74302
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 526947; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2022 | The c.5164T>G (p.F1722V) alteration is located in exon 42 (coding exon 42) of the CACNA1C gene. This alteration results from a T to G substitution at nucleotide position 5164, causing the phenylalanine (F) at amino acid position 1722 to be replaced by a valine (V). The p.F1722V alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 04, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
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;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
1.0, 0.0020, 0.61, 0.0030, 1.0, 0.28, 0.99, 0.99, 1.0, 0.99
.;D;B;P;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4
MutPred
0.31
.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at F1766 (P = 0.0679);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
MPC
0.26
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