rs756829999

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):​c.5339G>A​(p.Arg1780His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

1
5
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.566
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 -6 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.2433615).
BP6
Variant 12-2679691-G-A is Benign according to our data. Variant chr12-2679691-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 945968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkuse as main transcriptc.5339G>A p.Arg1780His missense_variant 42/47 ENST00000399655.6 NP_000710.5
CACNA1CNM_001167623.2 linkuse as main transcriptc.5339G>A p.Arg1780His missense_variant 42/47 ENST00000399603.6 NP_001161095.1
CACNA1C-AS1NR_045725.1 linkuse as main transcriptn.334-1794C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkuse as main transcriptc.5339G>A p.Arg1780His missense_variant 42/475 NM_001167623.2 ENSP00000382512 Q13936-37
CACNA1CENST00000399655.6 linkuse as main transcriptc.5339G>A p.Arg1780His missense_variant 42/471 NM_000719.7 ENSP00000382563 Q13936-12
CACNA1C-AS1ENST00000501371.5 linkuse as main transcriptn.295-1794C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000124
AC:
3
AN:
242558
Hom.:
0
AF XY:
0.0000152
AC XY:
2
AN XY:
131948
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000562
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000919
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1459866
Hom.:
0
Cov.:
32
AF XY:
0.00000826
AC XY:
6
AN XY:
726072
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000449
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000757
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

CACNA1C-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 16, 2022The CACNA1C c.5339G>A variant is predicted to result in the amino acid substitution p.Arg1780His. This variant has been reported in the heterozygous state in a 57 year old asymptomatic male but diagnosed with Brugada syndrome (saddle-back type) pattern ECG at an annual health check-up (Case 4, Fukuyama et al. 2013. PubMed ID: 23575362). This variant has also been reported in a registry of variants associated with Brugada syndrome (Supplementary Table 1, Chen et al. 2019. PubMed ID: 30662450) and was reported as a variant of uncertain significance in a study of genetics associated with Brugada syndrome (Campuzano et al. 2019. PubMed ID: 30821013). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-2788857-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 18, 2019The p.R1780H variant (also known as c.5339G>A), located in coding exon 42 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5339. The arginine at codon 1780 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in a Japanese cohort in an individual with Brugada syndrome sign on ECG; however, the patient was asymptomatic and family history information was not available (Fukuyama M et al. Circ. J., 2013 Apr;77:1799-806). This amino acid position is poorly conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.044
T
BayesDel_noAF
Uncertain
0.0
CADD
Benign
4.1
DANN
Benign
0.93
DEOGEN2
Benign
0.0039
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.96
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Pathogenic
0.72
D
MetaRNN
Benign
0.24
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
-0.075
T
MutationAssessor
Benign
1.0
.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.87
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Uncertain
0.53
Sift
Benign
0.21
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.080
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, 0.0020
.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4
0.34
MutPred
0.37
.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at Y1832 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.91
MPC
0.24
ClinPred
0.044
T
GERP RS
1.4
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs756829999; hg19: chr12-2788857; COSMIC: COSV59697447; COSMIC: COSV59697447; API