12-2053574-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000719.7(CACNA1C):ā€‹c.12G>Cā€‹(p.Glu4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,312 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 (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

4
5
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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=0.2046144).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.12G>C p.Glu4Asp missense_variant Exon 1 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.12G>C p.Glu4Asp missense_variant Exon 1 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000406454.8 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000347598.9 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000399638.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.12G>C p.Glu4Asp missense_variant Exon 1 of 46 ENSP00000507309.1 Q13936-19
CACNA1CENST00000682544.1 linkc.140-61650G>C intron_variant Intron 1 of 49 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000683824.1 linkc.140-61650G>C intron_variant Intron 1 of 47 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000682462.1 linkc.140-61650G>C intron_variant Intron 1 of 46 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.140-61650G>C intron_variant Intron 1 of 46 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.140-61650G>C intron_variant Intron 1 of 46 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.140-61650G>C intron_variant Intron 1 of 46 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000480911.6 linkn.12G>C non_coding_transcript_exon_variant Exon 1 of 27 5 ENSP00000437936.2 F5H638

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1448312
Hom.:
0
Cov.:
32
AF XY:
0.00000139
AC XY:
1
AN XY:
719044
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000232
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:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1
Nov 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 4 of the CACNA1C protein (p.Glu4Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.017
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.48
N
M_CAP
Pathogenic
0.48
D
MetaRNN
Benign
0.20
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
0.23
D
MutationAssessor
Benign
0.69
.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.86
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.93, 0.43, 0.59, 0.53, 0.27
.;P;.;B;P;P;P;P;P;P;P;P;B;P;P;P;.;P;P;.;.;.;.
Vest4
0.17
MutPred
0.15
Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);Gain of catalytic residue at R7 (P = 0.1002);
MVP
0.74
MPC
2.1
ClinPred
0.75
D
GERP RS
1.9
gMVP
0.64

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: rs2052987294; hg19: chr12-2162740; API