rs542914369

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):c.5671G>C(p.Ala1891Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,609,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.64

Publications

5 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07022217).

BP6

Variant 12-2685833-G-C is Benign according to our data. Variant chr12-2685833-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 279723.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.6010G>C	p.Ala2004Pro	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5884G>C	p.Ala1962Pro	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5851G>C	p.Ala1951Pro	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5836G>C	p.Ala1946Pro	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5815G>C	p.Ala1939Pro	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5794G>C	p.Ala1932Pro	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5776G>C	p.Ala1926Pro	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5776G>C	p.Ala1926Pro	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5755G>C	p.Ala1919Pro	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5746G>C	p.Ala1916Pro	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5731G>C	p.Ala1911Pro	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5728G>C	p.Ala1910Pro	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5728G>C	p.Ala1910Pro	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5728G>C	p.Ala1910Pro	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5722G>C	p.Ala1908Pro	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5713G>C	p.Ala1905Pro	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5695G>C	p.Ala1899Pro	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5695G>C	p.Ala1899Pro	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5689G>C	p.Ala1897Pro	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5662G>C	p.Ala1888Pro	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5638G>C	p.Ala1880Pro	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248772

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.000323

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1457630

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725362

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33418

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108154

Other (OTH)

AF:

0.0000332

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000656

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.0000712

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Uncertain:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jan 07, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The A1891P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this variant was not observed in approximately 6,100 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 1000 Genomes Project reports A1891P was observed in approximately 0.1% of alleles from individuals of African background. The A1891P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating this region of the gene is not known to harbor pathogenic variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Long QT syndrome

Uncertain:1

Jan 13, 2025

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 proline, which is neutral and non-polar, at codon 1891 of the CACNA1C protein (p.Ala1891Pro). This variant is present in population databases (rs542914369, gnomAD 0.03%). 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: 279723). 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

Benign:1

Nov 10, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Uncertain

0.40

CardioboostArm

Benign

0.000026

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0022

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

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.61

M_CAP

Benign

0.084

MetaRNN

Benign

0.070

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

MetaSVM

Benign

-0.89

PhyloP100

1.6

PrimateAI

Benign

0.46

PROVEAN

Benign

0.45

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

REVEL

Benign

0.18

Sift

Benign

0.42

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

Sift4G

Benign

0.40

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

Polyphen

0.73, 0.0010, 0.0, 0.78, 0.81, 0.0060, 0.57, 0.70, 0.88, 0.95, 0.51

.;P;B;B;B;P;P;P;B;P;P;P;P;P;P;.;P;P;.;.;.;P;.

Vest4

0.34

MVP

0.63

MPC

0.29

ClinPred

0.017

GERP RS

2.3

gMVP

0.35

Mutation Taster

=84/16

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

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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