rs201049603

Positions:

chr12-2679550-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000719.7(CACNA1C):c.5198C>T(p.Ala1733Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1733A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.61

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:

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 links:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.08721954).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5432C>T	p.Ala1811Val	missense_variant	44/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.5198C>T	p.Ala1733Val	missense_variant	42/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5165C>T	p.Ala1722Val	missense_variant	41/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.5363C>T	p.Ala1788Val	missense_variant	43/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5342C>T	p.Ala1781Val	missense_variant	44/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5321C>T	p.Ala1774Val	missense_variant	42/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5198C>T	p.Ala1733Val	missense_variant	42/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5198C>T	p.Ala1733Val	missense_variant	42/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5288C>T	p.Ala1763Val	missense_variant	42/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5288C>T	p.Ala1763Val	missense_variant	42/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5288C>T	p.Ala1763Val	missense_variant	42/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5288C>T	p.Ala1763Val	missense_variant	42/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5282C>T	p.Ala1761Val	missense_variant	43/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5273C>T	p.Ala1758Val	missense_variant	43/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5258C>T	p.Ala1753Val	missense_variant	43/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5255C>T	p.Ala1752Val	missense_variant	42/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5255C>T	p.Ala1752Val	missense_variant	42/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5255C>T	p.Ala1752Val	missense_variant	42/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5249C>T	p.Ala1750Val	missense_variant	42/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5240C>T	p.Ala1747Val	missense_variant	42/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5222C>T	p.Ala1741Val	missense_variant	41/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5222C>T	p.Ala1741Val	missense_variant	41/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5216C>T	p.Ala1739Val	missense_variant	41/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5198C>T	p.Ala1733Val	missense_variant	42/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5189C>T	p.Ala1730Val	missense_variant	42/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5165C>T	p.Ala1722Val	missense_variant	41/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000243

AC:

AN:

246464

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133942

show subpopulations

Gnomad AFR exome

AF:

0.0000669

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460894

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

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

Alfa

AF:

0.0000321

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000236

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2023

Observed in an individual with drug-inducted LQTS (Ramirez et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23834499, 22584458, 32145446) -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1733 of the CACNA1C protein (p.Ala1733Val). This variant is present in population databases (rs201049603, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of CACNA1C-related conditions (PMID: 22584458, 32145446). This variant is also known as c.5222C>T, p.A1741V. ClinVar contains an entry for this variant (Variation ID: 190686). 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%. 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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.11

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.087

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

MetaSVM

Uncertain

-0.032

MutationAssessor

Benign

1.1

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.90

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

REVEL

Uncertain

0.31

Sift

Benign

0.21

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

Sift4G

Benign

0.33

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

Polyphen

0.12, 0.0020, 0.080, 0.28, 0.32, 0.049, 0.20, 0.45, 0.90

.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;P;B;.;.;.;P;.

Vest4

0.27

MVP

0.55

MPC

0.19

ClinPred

0.15

GERP RS

4.6

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Other links and lift over