rs1057518456

Variant names:

• chr12-2115304-C-G
• rs1057518456
• NM_000719.7:c.130C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-2115304-C-G
• chr12-2115304-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.130C>G​(p.Pro44Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000502 in 1,594,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.91

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33307993).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.220C>G	p.Pro74Ala	missense_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.130C>G	p.Pro44Ala	missense_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.79C>G	p.Pro27Ala	missense_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.130C>G		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 34

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

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1441832 Hom.: 0 Cov.: 32 AF XY: 0.00000559 AC XY: 4 AN XY: 715902

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: 0.00000543

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

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

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P44A variant in the CACNA1C gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P44A variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P44A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P44A as a variant of uncertain significance. -

Brugada syndrome Uncertain:1

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

not provided Uncertain:1

Jan 20, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the CACNA1C protein (p.Pro44Ala). This variant is not present in population databases (gnomAD no frequency). 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: 373514). 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 Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P44A variant (also known as c.130C>G), located in coding exon 2 of the CACNA1C gene, results from a C to G substitution at nucleotide position 130. The proline at codon 44 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	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;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.1	.;.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.8	D;D;D;D;N;D;D;D;D;D;N;D;D;D;D;D;N;D;N;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.083	T;D;T;T;D;D;T;T;T;D;D;T;T;D;T;D;D;D;T;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0, 0.0030, 0.0060	.;.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;.
Vest4		0.42, 0.55, 0.46, 0.54, 0.56, 0.53, 0.56, 0.55, 0.56, 0.45, 0.52, 0.56, 0.53, 0.54, 0.49, 0.55, 0.45, 0.57, 0.58, 0.55, 0.50
MVP		0.66
MPC		1.0
ClinPred		0.56	D
GERP RS		5.8
gMVP		0.71

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: rs1057518456; hg19: chr12-2224470;