NM_000719.7:c.5150C>T

Variant names:

• chr12-2679502-C-T
• rs201492706
• NM_000719.7:c.5150C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5150C>T​(p.Ala1717Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,609,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1717T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.62
• Publications: 9 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15280312).
• BP6: Variant 12-2679502-C-T is Benign according to our data. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989. Variant chr12-2679502-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 526989.
• BS2: High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5384C>T	p.Ala1795Val	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5117C>T	p.Ala1706Val	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5315C>T	p.Ala1772Val	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5294C>T	p.Ala1765Val	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5273C>T	p.Ala1758Val	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5240C>T	p.Ala1747Val	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5240C>T	p.Ala1747Val	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5240C>T	p.Ala1747Val	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5240C>T	p.Ala1747Val	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5234C>T	p.Ala1745Val	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5225C>T	p.Ala1742Val	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5210C>T	p.Ala1737Val	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5207C>T	p.Ala1736Val	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5207C>T	p.Ala1736Val	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5207C>T	p.Ala1736Val	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5201C>T	p.Ala1734Val	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5192C>T	p.Ala1731Val	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5174C>T	p.Ala1725Val	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5174C>T	p.Ala1725Val	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5168C>T	p.Ala1723Val	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5150C>T	p.Ala1717Val	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5141C>T	p.Ala1714Val	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5117C>T	p.Ala1706Val	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 243628 AF XY: 0.00000755

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1456958 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 20 AN XY: 724114

African (AFR) AF: 0.0000300 AC: 1 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000289 AC: 32 AN: 1108784

Other (OTH) AF: 0.0000166 AC: 1 AN: 60190

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74478

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long qt syndrome 8 Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C NM_000719.6 exon 42 p.Ala1717Val (c.5150C>T): This variant has not been reported in the literature but is present in 3/108592 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201492706). This variant is present in ClinVar (Variation ID:526989). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Jan 20, 2025

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 valine, which is neutral and non-polar, at codon 1717 of the CACNA1C protein (p.Ala1717Val). This variant is present in population databases (rs201492706, gnomAD 0.003%). 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: 526989). 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. -

Cardiovascular phenotype Benign:1

Nov 05, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
CardioboostArm	Benign	0.0000040
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.15	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	0.13	D
MutationAssessor	Benign	0.34	.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.6
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.057	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;D;D;D;.
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.045, 0.0, 0.018, 0.056, 0.035, 0.0040, 0.020, 0.029, 0.026, 0.061, 0.76	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;P;.
Vest4		0.21
MVP		0.65
MPC		0.19
ClinPred		0.24	T
GERP RS		3.7
gMVP		0.50
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201492706; hg19: chr12-2788668;