12-2493370-C-T

Position:

chr12-2493370-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000719.7(CACNA1C):c.1097C>T(p.Thr366Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 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. T366T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ: 6.4654 (greater than the threshold 3.09). Trascript score misZ: 7.2674 (greater than threshold 3.09). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1187C>T	p.Thr396Met	missense_variant	7/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.1097C>T	p.Thr366Met	missense_variant	7/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1187C>T	p.Thr396Met	missense_variant	7/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.1097C>T	p.Thr366Met	missense_variant	7/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1097C>T	p.Thr366Met	missense_variant	7/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.1097C>T	p.Thr366Met	missense_variant	7/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1187C>T	p.Thr396Met	missense_variant	7/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1187C>T	p.Thr396Met	missense_variant	7/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1187C>T	p.Thr396Met	missense_variant	7/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1187C>T	p.Thr396Met	missense_variant	7/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1097C>T	p.Thr366Met	missense_variant	7/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1097C>T	p.Thr366Met	missense_variant	7/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.1097C>T	p.Thr366Met	missense_variant	7/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.1097C>T	p.Thr366Met	missense_variant	7/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.1088C>T	p.Thr363Met	missense_variant	7/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1097C>T	p.Thr366Met	missense_variant	7/46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.1034C>T	p.Thr345Met	missense_variant	6/6			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.1097C>T		non_coding_transcript_exon_variant	7/27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250540

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135550

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2024

Reported in a patient with long QT syndrome in published literature; however, further clinical information was not provided (PMID: 31737537); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37198425, 31737537) -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

ClinVar contains an entry for this variant (Variation ID: 546362). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 31737537). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 366 of the CACNA1C protein (p.Thr366Met). 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 expected to disrupt CACNA1C protein function. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The p.T366M variant (also known as c.1097C>T), located in coding exon 7 of the CACNA1C gene, results from a C to T substitution at nucleotide position 1097. The threonine at codon 366 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in an arrhythmogenic disorders cohort (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

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

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.82

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

Uncertain

2.5

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

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

0.92

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D

Vest4

0.95

MutPred

0.61

Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);Gain of catalytic residue at L369 (P = 0);

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

4.9

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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