rs1555832882

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000719.7(CACNA1C):​c.2278G>A​(p.Glu760Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1C
NM_000719.7 missense

Scores

11
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.98
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 5 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 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.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.2368G>A p.Glu790Lys missense_variant Exon 16 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.2443G>A p.Glu815Lys missense_variant Exon 17 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.2368G>A p.Glu790Lys missense_variant Exon 16 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.2368G>A p.Glu790Lys missense_variant Exon 16 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.2368G>A p.Glu790Lys missense_variant Exon 16 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.2368G>A p.Glu790Lys missense_variant Exon 16 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.2353G>A p.Glu785Lys missense_variant Exon 17 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.2353G>A p.Glu785Lys missense_variant Exon 17 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.2269G>A p.Glu757Lys missense_variant Exon 16 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.2278G>A p.Glu760Lys missense_variant Exon 16 of 46 ENSP00000507309.1 Q13936-19
CACNA1CENST00000480911.6 linkn.*885G>A non_coding_transcript_exon_variant Exon 14 of 27 5 ENSP00000437936.2 F5H638
CACNA1CENST00000480911.6 linkn.*885G>A 3_prime_UTR_variant Exon 14 of 27 5 ENSP00000437936.2 F5H638

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Long QT syndrome Uncertain:1
Dec 02, 2024
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 lysine, which is basic and polar, at codon 760 of the CACNA1C protein (p.Glu760Lys). 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. ClinVar contains an entry for this variant (Variation ID: 526937). 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 expected to disrupt CACNA1C protein function with a positive 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
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.67
D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.87
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
1.1
D
MutationAssessor
Uncertain
2.9
.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-3.7
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 0.97, 0.89, 1.0, 1.0, 0.93, 1.0, 0.98, 0.99
.;D;D;P;D;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4
0.92
MutPred
0.45
.;Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);
MVP
0.97
MPC
2.3
ClinPred
1.0
D
GERP RS
4.7
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs1555832882; hg19: chr12-2693722; COSMIC: COSV100214579; API