rs1057518456

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.130C>G(p.Pro44Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000502 in 1,594,066 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. P44P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.91

Publications

1 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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C 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=0.33307993).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.79C>G	p.Pro27Ala	missense_variant	Exon 1 of 6			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.130C>G		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000416

AC:

AN:

1441832

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

715902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33012

American (AMR)

AF:

0.00

AC:

AN:

42264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25766

East Asian (EAS)

AF:

0.00

AC:

AN:

38480

South Asian (SAS)

AF:

0.00

AC:

AN:

83648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000543

AC:

AN:

1104108

Other (OTH)

AF:

0.00

AC:

AN:

59682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

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:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The P44A variant in the CACNA1C gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P44A variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P44A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P44A as a variant of uncertain significance. -

Brugada syndrome

Uncertain:1

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

not provided

Uncertain:1

Jan 20, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the CACNA1C protein (p.Pro44Ala). 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: 373514). 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 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. -

Cardiovascular phenotype

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P44A variant (also known as c.130C>G), located in coding exon 2 of the CACNA1C gene, results from a C to G substitution at nucleotide position 130. The proline at codon 44 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other 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

CardioboostArm

Benign

0.000091

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

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

Eigen

Benign

-0.032

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.011

MetaRNN

Benign

0.33

T;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

0.11

MutationAssessor

Benign

1.1

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

PhyloP100

3.9

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.8

D;D;D;D;N;D;D;D;D;D;N;D;D;D;D;D;N;D;N;D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.083

T;D;T;T;D;D;T;T;T;D;D;T;T;D;T;D;D;D;T;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010, 0.0, 0.0030, 0.0060

.;.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;.

Vest4

0.42, 0.55, 0.46, 0.54, 0.56, 0.53, 0.56, 0.55, 0.56, 0.45, 0.52, 0.56, 0.53, 0.54, 0.49, 0.55, 0.45, 0.57, 0.58, 0.55, 0.50

MVP

0.66

MPC

1.0

ClinPred

0.56

GERP RS

5.8

PromoterAI

-0.037

Neutral

(source)

gMVP

0.71

Mutation Taster

=59/41

polymorphism

(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

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