chr12-2512936-G-A

Position:

• chr12-2512936-G-A

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.1342G>A​(p.Asp448Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,611,310 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.99

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 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, 0.776
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1342G>A	p.Asp448Asn	missense_variant	9/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1342G>A	p.Asp448Asn	missense_variant	9/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1342G>A	p.Asp448Asn	missense_variant	9/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1432G>A	p.Asp478Asn	missense_variant	9/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1342G>A	p.Asp448Asn	missense_variant	9/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1342G>A	p.Asp448Asn	missense_variant	9/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1432G>A	p.Asp478Asn	missense_variant	9/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1342G>A	p.Asp448Asn	missense_variant	9/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1342G>A	p.Asp448Asn	missense_variant	9/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1342G>A	p.Asp448Asn	missense_variant	9/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1432G>A	p.Asp478Asn	missense_variant	9/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1432G>A	p.Asp478Asn	missense_variant	9/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1432G>A	p.Asp478Asn	missense_variant	9/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1432G>A	p.Asp478Asn	missense_variant	9/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1342G>A	p.Asp448Asn	missense_variant	9/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1342G>A	p.Asp448Asn	missense_variant	9/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1342G>A	p.Asp448Asn	missense_variant	9/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1342G>A	p.Asp448Asn	missense_variant	9/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1342G>A	p.Asp448Asn	missense_variant	9/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1342G>A	p.Asp448Asn	missense_variant	9/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1342G>A	p.Asp448Asn	missense_variant	9/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1342G>A	p.Asp448Asn	missense_variant	9/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1342G>A	p.Asp448Asn	missense_variant	9/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1333G>A	p.Asp445Asn	missense_variant	9/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1342G>A	p.Asp448Asn	missense_variant	9/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19550G>A		intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244268 Hom.: 0 AF XY: 0.00000756 AC XY: 1 AN XY: 132354

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: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459160 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725494

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2013	p.Asp448Asn (GAT>AAT): c.1342 G>A in exon 9 of the CACNA1C gene (NM_000719.6). The Asp448Asn variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp448Asn results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a position that is conserved across species. In silico analysis predicts Asp448Asn is probably damaging to the protein structure/function. The Asp448Asn variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with LQTS, indicating this region of the protein may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Asp448Asn is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 22, 2023

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: 190635). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 448 of the CACNA1C protein (p.Asp448Asn). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The p.D448N variant (also known as c.1342G>A), located in coding exon 9 of the CACNA1C gene, results from a G to A substitution at nucleotide position 1342. The aspartic acid at codon 448 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in an arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available 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	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.070	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.78	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	Pathogenic	3.7	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.70
MutPred		0.28		Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);Gain of catalytic residue at P449 (P = 0.0028);
MVP		0.91
MPC		2.2
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.80

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: rs786205746; hg19: chr12-2622102; COSMIC: COSV59742852;