rs765111782

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000719.7(CACNA1C):c.2452G>A(p.Ala818Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,559,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Publications

2 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03137636).

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2542G>A	p.Ala848Thr	missense_variant	Exon 17 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2617G>A	p.Ala873Thr	missense_variant	Exon 18 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2542G>A	p.Ala848Thr	missense_variant	Exon 17 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2542G>A	p.Ala848Thr	missense_variant	Exon 17 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2542G>A	p.Ala848Thr	missense_variant	Exon 17 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2542G>A	p.Ala848Thr	missense_variant	Exon 17 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2527G>A	p.Ala843Thr	missense_variant	Exon 18 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2527G>A	p.Ala843Thr	missense_variant	Exon 18 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2443G>A	p.Ala815Thr	missense_variant	Exon 17 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2452G>A	p.Ala818Thr	missense_variant	Exon 17 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1059G>A		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1059G>A		3_prime_UTR_variant	Exon 15 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1407508

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

695184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32410

American (AMR)

AF:

0.00

AC:

AN:

36564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24978

East Asian (EAS)

AF:

0.00

AC:

AN:

37174

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.0000240

AC:

AN:

1083338

Other (OTH)

AF:

0.00

AC:

AN:

58302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Jan 19, 2024

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 threonine, which is neutral and polar, at codon 818 of the CACNA1C protein (p.Ala818Thr). 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: 456954). 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) performed at Invitae 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

CardioboostArm

Benign

0.000028

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.011

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

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Benign

0.084

MetaRNN

Benign

0.031

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

-0.42

MutationAssessor

Benign

0.0

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

PhyloP100

1.4

PrimateAI

Benign

0.31

PROVEAN

Benign

1.2

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

1.0

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

0.69

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

Vest4

0.040

ClinPred

0.12

GERP RS

2.5

gMVP

0.23

Mutation Taster

=86/14

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over