12-2493304-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2PP3_ModerateBS2

The NM_000719.7(CACNA1C):c.1031C>T(p.Thr344Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T344T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.91

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1022C>T	p.Thr341Ile	missense_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.968C>T	p.Thr323Ile	missense_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.1031C>T		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111934

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Long QT syndrome

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 344 of the CACNA1C protein (p.Thr344Ile). 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: 191419). 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 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

0.94

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

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

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.92

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

1.1

MutationAssessor

Benign

0.0

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

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.4

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

0.91

Sift

Benign

0.060

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

Sift4G

Uncertain

0.042

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

Vest4

0.97

ClinPred

0.99

GERP RS

5.1

gMVP

0.99

Mutation Taster

=18/82

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