rs767204844
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4BS2
The NM_000719.7(CACNA1C):c.2550G>C(p.Glu850Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 missense
NM_000719.7 missense
Scores
1
9
7
Clinical Significance
Conservation
PhyloP100: 4.26
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000719.7
PP2
?
Missense variant where missense usually causes diseases, CACNA1C
BP4
?
Computational evidence support a benign effect (MetaRNN=0.35351548).
BS2
?
High AC in GnomAdExome at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.2550G>C | p.Glu850Asp | missense_variant | 19/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.2550G>C | p.Glu850Asp | missense_variant | 19/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.2550G>C | p.Glu850Asp | missense_variant | 19/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.2550G>C | p.Glu850Asp | missense_variant | 19/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248522Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134822
GnomAD3 exomes
AF:
AC:
5
AN:
248522
Hom.:
AF XY:
AC XY:
3
AN XY:
134822
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461374Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726918
GnomAD4 exome
AF:
AC:
20
AN:
1461374
Hom.:
Cov.:
31
AF XY:
AC XY:
10
AN XY:
726918
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ExAC
?
AF:
AC:
3
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 | Jan 05, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 850 of the CACNA1C protein (p.Glu850Asp). This variant is present in population databases (rs767204844, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 570288). 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: "Tolerated"; 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
CardioboostArm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
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
Pathogenic
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;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;N;N;D;N;D;D;D;N;D;N;D;D;D;N;D;N;D;D;N;D;D
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
1.0, 0.22, 0.043, 0.044, 0.088, 1.0, 1.0, 0.99, 0.91
.;D;B;B;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;D;.;P
Vest4
MutPred
0.34
.;Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);
MVP
MPC
1.4
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