chr12-2608578-A-C

Position:

• chr12-2608578-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_000719.7(CACNA1C):​c.3424A>C​(p.Ile1142Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.95

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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 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). GenCC has associacion of 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, 0.833
• BS2: High AC in GnomAdExome4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3574A>C	p.Ile1192Leu	missense_variant	28/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3424A>C	p.Ile1142Leu	missense_variant	27/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3589A>C	p.Ile1197Leu	missense_variant	28/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3484A>C	p.Ile1162Leu	missense_variant	28/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3424A>C	p.Ile1142Leu	missense_variant	27/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3424A>C	p.Ile1142Leu	missense_variant	27/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3514A>C	p.Ile1172Leu	missense_variant	27/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3514A>C	p.Ile1172Leu	missense_variant	27/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3514A>C	p.Ile1172Leu	missense_variant	27/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3514A>C	p.Ile1172Leu	missense_variant	27/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3499A>C	p.Ile1167Leu	missense_variant	28/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3484A>C	p.Ile1162Leu	missense_variant	28/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3499A>C	p.Ile1167Leu	missense_variant	28/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3424A>C	p.Ile1142Leu	missense_variant	27/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3424A>C	p.Ile1142Leu	missense_variant	27/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3415A>C	p.Ile1139Leu	missense_variant	27/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3424A>C	p.Ile1142Leu	missense_variant	27/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2031A>C		non_coding_transcript_exon_variant	25/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2031A>C		3_prime_UTR_variant	25/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250964 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135682

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727124

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: 0.0000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 24, 2019

Variant summary: CACNA1C c.3424A>C (p.Ile1142Leu) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250964 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3424A>C has been reported in the literature in one individual who may be affected by Arrhythmia (Adler_2016). The report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2018

The Ile1142Leu variant in the CACNA1C gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Although the Ile1142Leu results in a conservative substitution of one non-polar amino acid for another, the Ile1142 residue is conserved across species. In silico analysis predicts Ile1142Leu is possibly damaging to the proteins structure/function (Adzhubei I et al., 2010). The NHLBI ESP Exome Variant Server reports Ile1142Leu was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, Ile1142Leu occurs in a region of the CACNA1C gene with few reported mutations suggesting this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot determine whether Ile1142Leu in the CACNA1C gene is a disease-causing mutation or benign variant. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 190659). This missense change has been observed in individual(s) with an unspecified cardiac condition (PMID: 26743238). This variant is present in population databases (rs752247655, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1142 of the CACNA1C protein (p.Ile1142Leu). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2020

The p.I1142L variant (also known as c.3424A>C), located in coding exon 27 of the CACNA1C gene, results from an A to C substitution at nucleotide position 3424. The isoleucine at codon 1142 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in an arrhythmia cohort; however, clinical details were limited (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440). 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	0.27	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.83	D;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	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.090	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.98, 0.65, 0.97, 0.92, 0.96, 0.98, 0.98, 0.53, 0.93	.;D;P;D;P;D;D;D;D;P;D;D;D;D;P;D;.;D;D;.;.;.;D;.
Vest4		0.72
MutPred		0.48		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1163 (P = 0.0042);Gain of catalytic residue at S1163 (P = 0.0042);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.88
MPC		2.1
ClinPred		0.87	D
GERP RS		4.7
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

Other links and lift over

dbSNP: rs752247655; hg19: chr12-2717744;