rs111606207

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000719.7(CACNA1C):c.3234C>A(p.Asp1078Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,668 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D1078D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -2.29

Publications

2 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:

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

CACNA1C-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3060698).

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3384C>A	p.Asp1128Glu	missense_variant	Exon 27 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3399C>A	p.Asp1133Glu	missense_variant	Exon 27 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3294C>A	p.Asp1098Glu	missense_variant	Exon 27 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3324C>A	p.Asp1108Glu	missense_variant	Exon 26 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3324C>A	p.Asp1108Glu	missense_variant	Exon 26 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3324C>A	p.Asp1108Glu	missense_variant	Exon 26 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3324C>A	p.Asp1108Glu	missense_variant	Exon 26 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3309C>A	p.Asp1103Glu	missense_variant	Exon 27 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3294C>A	p.Asp1098Glu	missense_variant	Exon 27 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3309C>A	p.Asp1103Glu	missense_variant	Exon 27 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3225C>A	p.Asp1075Glu	missense_variant	Exon 26 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3234C>A	p.Asp1078Glu	missense_variant	Exon 26 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1841C>A		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1841C>A		3_prime_UTR_variant	Exon 24 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249226

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1111834

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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

Cov.:

ExAC

AF:

0.00000826

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1078 of the CACNA1C protein (p.Asp1078Glu). This variant is present in population databases (rs111606207, gnomAD 0.0009%). 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: 589764). 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 not expected to disrupt CACNA1C protein function with a negative predictive value of 80%. 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

Uncertain:1

Apr 18, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D1078E variant (also known as c.3234C>A), located in coding exon 26 of the CACNA1C gene, results from a C to A substitution at nucleotide position 3234. The aspartic acid at codon 1078 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

CardioboostArm

Benign

0.00020

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

1.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.0

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

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.31

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

0.52

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;L;L;.;.;.;.;.;.;.;.;.;.

PhyloP100

-2.3

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.60

Sift

Benign

0.15

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

Sift4G

Benign

0.18

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

Vest4

0.63

ClinPred

0.84

GERP RS

-5.8

gMVP

0.94

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over