4-113513860-C-G

Position:

• chr4-113513860-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001321571.2(CAMK2D):​c.873G>C​(p.Leu291Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2D NM_001321571.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.19

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]

CAMK2D (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-113513860-C-G is Pathogenic according to our data. Variant chr4-113513860-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1343379.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK2D	NM_001321571.2	c.873G>C	p.Leu291Phe	missense_variant	11/21	ENST00000511664.6	NP_001308500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2D	ENST00000511664.6	c.873G>C	p.Leu291Phe	missense_variant	11/21	2	NM_001321571.2	ENSP00000425824.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Pathogenic:2

Pathogenic, no assertion criteria provided	research	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with neurodevelopmental disorder (MONDO#0700092), CAMK2D-related (PMID: 38272033). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies showed this variant has a dominant negative effect (PMID: 38272033). Western blots showed HEK293T cells transfected with this variant had significant increase in CAMK2D protein level compared to HEK293T cells transfected with wildtype CAMK2D. Overexpression of CAMK2D-L291F showed very little autophosphorylation at Thr287. Overexpression of this variant in mice during prenatal neurodevelopment showed a neuronal migration deficit. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T;D;.;T;.;T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M;.;M;.;M;M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.028	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.0040	B;.;B;B;B;.;.;.;.;.;.
Vest4		0.71
MutPred		0.60		Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);Gain of glycosylation at T287 (P = 0.0138);.;
MVP		0.76
MPC		1.2
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-114435016;