rs1060503447

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.2333T>C(p.Leu778Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L778V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.92

Publications

3 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: 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.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2423T>C	p.Leu808Pro	missense_variant	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2498T>C	p.Leu833Pro	missense_variant	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2423T>C	p.Leu808Pro	missense_variant	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2423T>C	p.Leu808Pro	missense_variant	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2423T>C	p.Leu808Pro	missense_variant	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2423T>C	p.Leu808Pro	missense_variant	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2408T>C	p.Leu803Pro	missense_variant	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2408T>C	p.Leu803Pro	missense_variant	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2324T>C	p.Leu775Pro	missense_variant	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2333T>C	p.Leu778Pro	missense_variant	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*940T>C		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*940T>C		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108924

Other (OTH)

AF:

0.00

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 778 of the CACNA1C protein (p.Leu778Pro). 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: 411729). 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%. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 19061337, 23145875). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

CardioboostArm

Benign

0.000051

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.71

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

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.5

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

PhyloP100

4.9

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.74

Sift

Benign

0.12

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

0.24

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, 1.0, 0.012, 0.020, 0.0040, 0.027, 1.0, 1.0

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

Vest4

0.69

MutPred

0.48

.;Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);

MVP

0.96

MPC

1.7

ClinPred

0.91

GERP RS

4.7

gMVP

0.96

Mutation Taster

=7/93

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over