rs369680588

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000719.7(CACNA1C):c.1348G>C(p.Glu450Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,662 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. E450E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.14

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1339G>C	p.Glu447Gln	missense_variant	Exon 9 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.1113+19556G>C		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1458662

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

85354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1110552

Other (OTH)

AF:

0.00

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 450 of the CACNA1C protein (p.Glu450Gln). 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: 411717). 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 expected to disrupt CACNA1C protein function with a positive 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

CardioboostArm

Uncertain

0.27

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

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

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.64

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

0.97

MutationAssessor

Uncertain

2.5

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

PhyloP100

8.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.5

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

REVEL

Pathogenic

0.66

Sift

Uncertain

0.018

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

Sift4G

Benign

0.084

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

Polyphen

1.0, 0.73, 0.74, 0.97, 1.0, 0.75, 1.0

.;D;.;P;P;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D

Vest4

0.54

MVP

0.87

MPC

1.7

ClinPred

0.98

GERP RS

4.4

gMVP

0.84

Mutation Taster

=51/49

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