12-2566522-A-G

Position:

• chr12-2566522-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000719.7(CACNA1C):​c.1609A>G​(p.Asn537Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.923
• PP5: Variant 12-2566522-A-G is Pathogenic according to our data. Variant chr12-2566522-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1609A>G	p.Asn537Asp	missense_variant	12/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1609A>G	p.Asn537Asp	missense_variant	12/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1609A>G	p.Asn537Asp	missense_variant	12/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.1609A>G	p.Asn537Asp	missense_variant	12/47	1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant has been reported as assumed (i.e. paternity and maternity not confirmed) de novo by an outside laboratory. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CACNA1C related disorder (ClinVar ID: VCV000521136). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.1609A>G (p.N537D) alteration is located in exon 12 (coding exon 12) of the CACNA1C gene. This alteration results from an A to G substitution at nucleotide position 1609, causing the asparagine (N) at amino acid position 537 to be replaced by an aspartic acid (D)._x000D_ _x000D_ Based on the available evidence, the CACNA1C c.1609A>G (p.N537D) alteration is classified as likely pathogenic for CACNA1C-related neurodevelopmental disorder; however, its clinical significance for Timothy syndrome and CACNA1C-related long QT syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The L-type Cav1.2 channel (encoded by CACNA1C) consists of four homologous domains, each containing six transmembrane segments S1-S6. Segments S1-S4 form the voltage-sensing domain. The p.N537 amino acid is located in transmembrane segment S1 of domain II. Structural modeling performed in house at Ambry Genetics suggests that the p.N537 amino acid is essential for Cav1.2 function as a voltage-dependent calcium channel. The p.N537D alteration may affect the gating of the Cav1.2 channel and transform the channel into a proton channel (Ramsey, 2010; Musset, 2011). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.92	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	4.2	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	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	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	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, 0.99, 1.0, 1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.95
MutPred		0.57		.;Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		2.8
gMVP		1.0

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: rs1467561684; hg19: chr12-2675688;