Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_000719.7(CACNA1C):c.1823C>A(p.Thr608Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T608I) has been classified as Uncertain significance.
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]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a topological_domain Extracellular (size 8) in uniprot entity CAC1C_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) 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, 0.794
.;Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);