rs367895193

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The ENST00000399655.6(CACNA1C):​c.3862G>A​(p.Ala1288Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,581,326 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1288S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

CACNA1C
ENST00000399655.6 missense

Scores

6
5
6

Clinical Significance

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

Conservation

PhyloP100: 9.81
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]

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 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=0.2833093).
BP6
Variant 12-2634330-G-A is Benign according to our data. Variant chr12-2634330-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190664.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BS2
High AC in GnomAdExome4 at 69 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkuse as main transcriptc.3862G>A p.Ala1288Thr missense_variant 30/47 ENST00000399655.6 NP_000710.5
CACNA1CNM_001167623.2 linkuse as main transcriptc.3912+618G>A intron_variant ENST00000399603.6 NP_001161095.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1CENST00000399655.6 linkuse as main transcriptc.3862G>A p.Ala1288Thr missense_variant 30/471 NM_000719.7 ENSP00000382563 Q13936-12
CACNA1CENST00000399603.6 linkuse as main transcriptc.3912+618G>A intron_variant 5 NM_001167623.2 ENSP00000382512 Q13936-37

Frequencies

GnomAD3 genomes
AF:
0.0000265
AC:
4
AN:
150724
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000295
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000817
AC:
17
AN:
207986
Hom.:
0
AF XY:
0.0000539
AC XY:
6
AN XY:
111214
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00161
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000223
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000482
AC:
69
AN:
1430602
Hom.:
0
Cov.:
29
AF XY:
0.0000466
AC XY:
33
AN XY:
708658
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00172
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000123
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000183
Gnomad4 OTH exome
AF:
0.0000506
GnomAD4 genome
AF:
0.0000265
AC:
4
AN:
150724
Hom.:
0
Cov.:
29
AF XY:
0.0000272
AC XY:
2
AN XY:
73486
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000253
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000664
AC:
8

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 30, 2023Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 27, 2022This 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
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Pathogenic
0.75
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.3
.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-2.2
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Pathogenic
0.66
Sift
Benign
0.057
T;D;D;T;D;T;D;D;T;T;T;D;T;T;T;T
Sift4G
Benign
0.095
T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T
Polyphen
0.77, 0.56, 1.0, 0.65, 0.32, 0.51
.;P;P;D;P;P;B;P;D;P;P;P;D;.;P;.
Vest4
0.74
MutPred
0.39
.;.;.;.;.;.;.;.;Gain of catalytic residue at V1339 (P = 0.0032);.;.;.;.;.;.;.;
MVP
0.88
MPC
1.0
ClinPred
0.25
T
GERP RS
5.5
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs367895193; hg19: chr12-2743496; API