4-113517631-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAMK2D NM_001321571.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89

Genes affected

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]

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK2D	NM_001321571.2	c.628G>A	p.Gly210Arg	missense_variant	9/21	ENST00000511664.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK2D	ENST00000511664.6	c.628G>A	p.Gly210Arg	missense_variant	9/21	2	NM_001321571.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1421812 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 709828

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;in vivo;research

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Feb 08, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;.;M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	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;.
Polyphen		1.0	D;.;D;D;D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.91		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);.;
MVP		0.69
MPC		2.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs867010473; hg19: chr4-114438787;