Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001321571.2(CAMK2D):c.628G>A(p.Gly210Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
CAMK2D (HGNC:1462): (calcium/calmodulin dependent protein kinase II delta) The product of this gene belongs to the serine/threonine protein kinase family and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. In mammalian cells, the enzyme is composed of four different chains: alpha, beta, gamma, and delta. The product of this gene is a delta chain. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Distinct isoforms of this chain have different expression patterns.[provided by RefSeq, Nov 2008]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 4-113517631-C-T is Pathogenic according to our data. Variant chr4-113517631-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2442394.Status of the report is criteria_provided_single_submitter, 1 stars.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: in vitro;in vivo;research
The p.(Gly210Arg) variant in CAMK2D is de novo, absent from large population studies and predicted pathogenic by most bioinformatics programs (CADD, REVEL, Metadome...). Besides, it affects the catalytic domain of CAMK2D, and is close to other variants identified in individuals with similar phenotype, and classified pathogenic. Additionally, in vitro functional studies indicate that the p.(Gly210Arg) variant increases phosphotransferase activity of CAMK2, and in vivo functional studies in mouse brain embryo showed that it causes severe migration deficit. In summary, the p.(Gly210Arg) variant meets our criteria to be classified as pathogenic. -
Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);.;