12-2679461-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000719.7(CACNA1C):c.5109C>G(p.Phe1703Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,423,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F1703F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.0920

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 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5343C>G	p.Phe1781Leu	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5076C>G	p.Phe1692Leu	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5274C>G	p.Phe1758Leu	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5253C>G	p.Phe1751Leu	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5232C>G	p.Phe1744Leu	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5199C>G	p.Phe1733Leu	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5199C>G	p.Phe1733Leu	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5199C>G	p.Phe1733Leu	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5199C>G	p.Phe1733Leu	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5193C>G	p.Phe1731Leu	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5184C>G	p.Phe1728Leu	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5169C>G	p.Phe1723Leu	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5166C>G	p.Phe1722Leu	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5166C>G	p.Phe1722Leu	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5166C>G	p.Phe1722Leu	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5160C>G	p.Phe1720Leu	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5151C>G	p.Phe1717Leu	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5133C>G	p.Phe1711Leu	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5133C>G	p.Phe1711Leu	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5127C>G	p.Phe1709Leu	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5109C>G	p.Phe1703Leu	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5100C>G	p.Phe1700Leu	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5076C>G	p.Phe1692Leu	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

208594

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1423848

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

703654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32724

American (AMR)

AF:

0.00

AC:

AN:

41698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23982

East Asian (EAS)

AF:

0.00

AC:

AN:

38646

South Asian (SAS)

AF:

0.00

AC:

AN:

79638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51104

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00000275

AC:

AN:

1091648

Other (OTH)

AF:

0.00

AC:

AN:

58786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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.:

Alfa

AF:

0.00

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Timothy syndrome

Uncertain:1

Aug 06, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Jul 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 1319953). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1703 of the CACNA1C protein (p.Phe1703Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostArm

Benign

0.0025

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

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

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.71

M_CAP

Pathogenic

0.32

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

0.76

MutationAssessor

Uncertain

2.1

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

PhyloP100

-0.092

PrimateAI

Pathogenic

0.85

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;.

REVEL

Uncertain

0.64

Sift

Benign

0.16

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

Sift4G

Benign

0.15

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

Polyphen

1.0, 0.049, 0.010, 0.12, 1.0, 0.99, 1.0, 0.99

.;D;B;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D;.

Vest4

0.51

MutPred

0.50

.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at N1753 (P = 5e-04);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.98

MPC

0.22

ClinPred

0.80

GERP RS

-3.0

gMVP

0.64

Mutation Taster

=30/70

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over