rs368700869

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000719.7(CACNA1C):c.5065G>A(p.Ala1689Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1689S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.01

Publications

0 publications found

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 links:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5299G>A	p.Ala1767Thr	missense_variant	Exon 43 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5032G>A	p.Ala1678Thr	missense_variant	Exon 40 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5230G>A	p.Ala1744Thr	missense_variant	Exon 42 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5209G>A	p.Ala1737Thr	missense_variant	Exon 43 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5188G>A	p.Ala1730Thr	missense_variant	Exon 41 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5155G>A	p.Ala1719Thr	missense_variant	Exon 41 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5155G>A	p.Ala1719Thr	missense_variant	Exon 41 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5155G>A	p.Ala1719Thr	missense_variant	Exon 41 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5155G>A	p.Ala1719Thr	missense_variant	Exon 41 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5149G>A	p.Ala1717Thr	missense_variant	Exon 42 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5140G>A	p.Ala1714Thr	missense_variant	Exon 42 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5125G>A	p.Ala1709Thr	missense_variant	Exon 42 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5122G>A	p.Ala1708Thr	missense_variant	Exon 41 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5122G>A	p.Ala1708Thr	missense_variant	Exon 41 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5122G>A	p.Ala1708Thr	missense_variant	Exon 41 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5116G>A	p.Ala1706Thr	missense_variant	Exon 41 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5107G>A	p.Ala1703Thr	missense_variant	Exon 41 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5089G>A	p.Ala1697Thr	missense_variant	Exon 40 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5089G>A	p.Ala1697Thr	missense_variant	Exon 40 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5083G>A	p.Ala1695Thr	missense_variant	Exon 40 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5056G>A	p.Ala1686Thr	missense_variant	Exon 41 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5032G>A	p.Ala1678Thr	missense_variant	Exon 40 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249216

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111820

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2013

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala1689Thr (GCT>ACT): c.5065 G>A in exon 41 of the CACNA1C gene (NM_000719.6). The Ala1689Thr variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala1689Thr results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue at a position that is conserved across species. The Ala1689Thr variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, in silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Furthermore, no mutations affecting nearby residues have been reported in association with LQTS, indicating this region of the protein may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Ala1689Thr is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).

CACNA1C-related disorder

Uncertain:1

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CACNA1C c.5065G>A variant is predicted to result in the amino acid substitution p.Ala1689Thr. This variant has been reported in an individual with aborted sudden death. Functionals studies of this variant showed no major alterations of the channel function (Blancard M et al 2018. PubMed ID: 30279520). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Timothy syndrome

Uncertain:1

Apr 17, 2019

MVZ Martinsried, Medicover Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Long QT syndrome

Uncertain:1

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1689 of the CACNA1C protein (p.Ala1689Thr). This variant is present in population databases (rs368700869, gnomAD 0.01%). This missense change has been observed in individual(s) with aborted sudden death (PMID: 30279520). ClinVar contains an entry for this variant (Variation ID: 190677). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. Experimental studies have shown that this missense change does not substantially affect CACNA1C function (PMID: 30279520). 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.

Cardiovascular phenotype

Benign:1

Aug 27, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

AlphaMissense

Benign

0.17

CardioboostArm

Benign

0.000026

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.43

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

0.73

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

7.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.

Sift

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.65

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Vest4

0.54

ClinPred

0.40

GERP RS

4.5

gMVP

0.55

Mutation Taster

=22/78

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over