rs926027867

Positions:

• chr5-150251808-G-A
• chr5-150251808-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_015981.4(CAMK2A):​c.635C>T​(p.Pro212Leu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P212Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2A NM_015981.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

Genes affected

CAMK2A (HGNC:1460): (calcium/calmodulin dependent protein kinase II alpha) The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2018]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150251808-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAMK2A. . Gene score misZ 4.6751 (greater than the threshold 3.09). Trascript score misZ 6.103 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal recessive 63, intellectual disability, autosomal dominant 40, autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 53.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 5-150251808-G-A is Pathogenic according to our data. Variant chr5-150251808-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 430916.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
CAMK2A	NM_015981.4	c.635C>T	p.Pro212Leu	missense_variant	9/19	ENST00000671881.1	NP_057065.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2A	ENST00000671881.1	c.635C>T	p.Pro212Leu	missense_variant	9/19		NM_015981.4	ENSP00000500386	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 53 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 CAMK2A-related intellectual disability. Missense variants have been shown to either impair or enhance autophosphorylation, or result in reduced protein expression (PMID: 28130356, 29784083, 29560374). (I) 0107 - This gene is associated with autosomal dominant disease. However, an isolated example of a family with autosomal recessive CAMK2A-related intellectual disability has been reported (PMID: 29784083). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (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 uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to a glutamine has been reported once as de novo in an individual with intellectual disability (PMID: 29560374). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and de novo in three individuals with intellectual disability (ClinVar, PMID: 29100089). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 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 -
Pathogenic, criteria provided, single submitter	clinical testing	Palindrome, Gene Kavoshgaran Aria	Jul 12, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 26, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant facilitates aberrant Ca2+/CaM-dependent activation of CaMKII leading to neuronal dysregulation (Fujii et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29100089, 32600977, 35982159, 35982160, 35043465, 33774142, 36028527, 36117912, 37510258) -

Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Jul 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.89		Gain of catalytic residue at P212 (P = 0.0084);Gain of catalytic residue at P212 (P = 0.0084);
MVP		0.90
MPC		2.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.99

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: rs926027867; hg19: chr5-149631371; COSMIC: COSV100804629; COSMIC: COSV100804629;