12-2679502-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000719.7(CACNA1C):​c.5150C>T​(p.Ala1717Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,609,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1717G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

5
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.62
Variant links:
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]
CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
BP4
Computational evidence support a benign effect (MetaRNN=0.15280312).
BS2
High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.5384C>T p.Ala1795Val missense_variant Exon 44 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.5117C>T p.Ala1706Val missense_variant Exon 41 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.5315C>T p.Ala1772Val missense_variant Exon 43 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.5294C>T p.Ala1765Val missense_variant Exon 44 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.5273C>T p.Ala1758Val missense_variant Exon 42 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.5240C>T p.Ala1747Val missense_variant Exon 42 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.5240C>T p.Ala1747Val missense_variant Exon 42 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.5240C>T p.Ala1747Val missense_variant Exon 42 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.5240C>T p.Ala1747Val missense_variant Exon 42 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.5234C>T p.Ala1745Val missense_variant Exon 43 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.5225C>T p.Ala1742Val missense_variant Exon 43 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.5210C>T p.Ala1737Val missense_variant Exon 43 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.5207C>T p.Ala1736Val missense_variant Exon 42 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.5207C>T p.Ala1736Val missense_variant Exon 42 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.5207C>T p.Ala1736Val missense_variant Exon 42 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.5201C>T p.Ala1734Val missense_variant Exon 42 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.5192C>T p.Ala1731Val missense_variant Exon 42 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.5174C>T p.Ala1725Val missense_variant Exon 41 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.5174C>T p.Ala1725Val missense_variant Exon 41 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.5168C>T p.Ala1723Val missense_variant Exon 41 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.5150C>T p.Ala1717Val missense_variant Exon 42 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.5141C>T p.Ala1714Val missense_variant Exon 42 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.5117C>T p.Ala1706Val missense_variant Exon 41 of 46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000123
AC:
3
AN:
243628
Hom.:
0
AF XY:
0.00000755
AC XY:
1
AN XY:
132502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000273
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1456958
Hom.:
0
Cov.:
31
AF XY:
0.0000276
AC XY:
20
AN XY:
724114
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000289
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021CACNA1C NM_000719.6 exon 42 p.Ala1717Val (c.5150C>T): This variant has not been reported in the literature but is present in 3/108592 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201492706). This variant is present in ClinVar (Variation ID:526989). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 01, 2021- -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2025This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1717 of the CACNA1C protein (p.Ala1717Val). This variant is present in population databases (rs201492706, gnomAD 0.003%). 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: 526989). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 80%. 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. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 05, 2021This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
0.0022
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.014
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.083
FATHMM_MKL
Uncertain
0.90
D
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.15
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
0.13
D
MutationAssessor
Benign
0.34
.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.31
T
PROVEAN
Uncertain
-2.5
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Benign
0.28
Sift
Benign
0.057
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;D;D;D;.
Sift4G
Benign
0.41
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.045, 0.0, 0.018, 0.056, 0.035, 0.0040, 0.020, 0.029, 0.026, 0.061, 0.76
.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;P;.
Vest4
0.21
MVP
0.65
MPC
0.19
ClinPred
0.24
T
GERP RS
3.7
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201492706; hg19: chr12-2788668; API