rs766023530

Variant names:

• chr12-2607105-G-A
• rs766023530
• NM_000719.7:c.3331G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2607105-G-A
• chr12-2607105-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000719.7(CACNA1C):​c.3331G>A​(p.Val1111Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 9.60

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a region_of_interest Dihydropyridine binding (size 89) in uniprot entity CAC1C_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BS2: High AC in GnomAdExome4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3481G>A	p.Val1161Ile	missense_variant	Exon 27 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3496G>A	p.Val1166Ile	missense_variant	Exon 27 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3391G>A	p.Val1131Ile	missense_variant	Exon 27 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3421G>A	p.Val1141Ile	missense_variant	Exon 26 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3421G>A	p.Val1141Ile	missense_variant	Exon 26 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3421G>A	p.Val1141Ile	missense_variant	Exon 26 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3421G>A	p.Val1141Ile	missense_variant	Exon 26 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3406G>A	p.Val1136Ile	missense_variant	Exon 27 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3391G>A	p.Val1131Ile	missense_variant	Exon 27 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3406G>A	p.Val1136Ile	missense_variant	Exon 27 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3322G>A	p.Val1108Ile	missense_variant	Exon 26 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3331G>A	p.Val1111Ile	missense_variant	Exon 26 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1938G>A		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1938G>A		3_prime_UTR_variant	Exon 24 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248228 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134632

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: 0.0000465

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 726868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sudden unexplained death Uncertain:1

Oct 04, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

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

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Uncertain:1

May 18, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 -

Timothy syndrome Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Feb 16, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#411719; Landrum et al., 2016) -

Long QT syndrome Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1111 of the CACNA1C protein (p.Val1111Ile). This variant is present in population databases (rs766023530, gnomAD 0.004%). 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: 411719). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1111I variant (also known as c.3331G>A), located in coding exon 26 of the CACNA1C gene, results from a G to A substitution at nucleotide position 3331. The valine at codon 1111 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	.;.;.;.;.;.;.;.;.;.;.;L;L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.93	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.036	D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.98, 0.98, 0.96, 1.0, 0.95, 1.0, 0.99	.;D;D;D;D;D;D;D;D;D;D;D;D;P;D;D;.;D;D;.;.;.;D
Vest4		0.65
MutPred		0.55		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1132 (P = 0);Gain of catalytic residue at S1132 (P = 0);.;.;.;.;.;.;.;.;.;.;
MVP		0.80
MPC		1.7
ClinPred		0.90	D
GERP RS		4.9
gMVP		0.92

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

Other links and lift over

dbSNP: rs766023530; hg19: chr12-2716271; COSMIC: COSV59751504; COSMIC: COSV59751504;