12-2679450-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

The NM_000719.7(CACNA1C):​c.5098G>A​(p.Gly1700Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,560,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

11
3
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 9.30
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 -3 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.833
BP6
Variant 12-2679450-G-A is Benign according to our data. Variant chr12-2679450-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526905.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkc.5098G>A p.Gly1700Ser missense_variant 42/47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.5098G>A p.Gly1700Ser missense_variant 42/47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.5098G>A p.Gly1700Ser missense_variant 42/475 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.5098G>A p.Gly1700Ser missense_variant 42/471 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.5332G>A p.Gly1778Ser missense_variant 44/50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.5098G>A p.Gly1700Ser missense_variant 42/485 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.5065G>A p.Gly1689Ser missense_variant 41/475 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.5263G>A p.Gly1755Ser missense_variant 43/48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.5242G>A p.Gly1748Ser missense_variant 44/491 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.5221G>A p.Gly1741Ser missense_variant 42/471 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.5098G>A p.Gly1700Ser missense_variant 42/481 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.5098G>A p.Gly1700Ser missense_variant 42/485 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.5188G>A p.Gly1730Ser missense_variant 42/47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.5188G>A p.Gly1730Ser missense_variant 42/47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.5188G>A p.Gly1730Ser missense_variant 42/47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.5188G>A p.Gly1730Ser missense_variant 42/47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.5182G>A p.Gly1728Ser missense_variant 43/481 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.5173G>A p.Gly1725Ser missense_variant 43/485 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.5158G>A p.Gly1720Ser missense_variant 43/481 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.5155G>A p.Gly1719Ser missense_variant 42/471 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.5155G>A p.Gly1719Ser missense_variant 42/471 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.5155G>A p.Gly1719Ser missense_variant 42/471 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.5149G>A p.Gly1717Ser missense_variant 42/471 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.5140G>A p.Gly1714Ser missense_variant 42/47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.5122G>A p.Gly1708Ser missense_variant 41/461 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.5122G>A p.Gly1708Ser missense_variant 41/461 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.5116G>A p.Gly1706Ser missense_variant 41/461 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.5098G>A p.Gly1700Ser missense_variant 42/471 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.5098G>A p.Gly1700Ser missense_variant 42/471 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.5098G>A p.Gly1700Ser missense_variant 42/471 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.5098G>A p.Gly1700Ser missense_variant 42/471 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.5098G>A p.Gly1700Ser missense_variant 42/47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.5089G>A p.Gly1697Ser missense_variant 42/47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.5065G>A p.Gly1689Ser missense_variant 41/46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152176
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000580
AC:
11
AN:
189716
Hom.:
0
AF XY:
0.0000690
AC XY:
7
AN XY:
101378
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000338
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:
0.000107
Gnomad OTH exome
AF:
0.000207
GnomAD4 exome
AF:
0.000132
AC:
186
AN:
1408372
Hom.:
0
Cov.:
31
AF XY:
0.000133
AC XY:
92
AN XY:
694264
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000500
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000525
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000157
Gnomad4 OTH exome
AF:
0.000189
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000605
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000665
AC:
8

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 18, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 21, 2024Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Timothy syndrome;C2678478:Brugada syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 29, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1700 of the CACNA1C protein (p.Gly1700Ser). This variant is present in population databases (rs761966966, gnomAD 0.01%). 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: 526905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 01, 2019Variant summary: CACNA1C c.5098G>A (p.Gly1700Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 216132 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.5098G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 21, 2024This 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
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.017
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
3.0
.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.2
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Pathogenic
0.78
Sift
Uncertain
0.014
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G
Benign
0.11
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, 0.99, 0.88, 0.78, 0.99
.;D;D;P;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4
0.86
MutPred
0.57
.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at N1753 (P = 0.001);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.97
MPC
0.34
ClinPred
0.61
D
GERP RS
4.4
gMVP
0.67

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: rs761966966; hg19: chr12-2788616; API