rs926027867

Variant names:

• chr5-150251808-G-A
• rs926027867
• NM_015981.4:c.635C>T

Your query was ambiguous. Multiple possible variants found:

• 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 the CAMK2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.6751 (above the threshold of 3.09). Trascript score misZ: 6.103 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
CAMK2A	NM_015981.4	c.635C>T	p.Pro212Leu	missense_variant	Exon 9 of 19	ENST00000671881.1	NP_057065.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK2A	ENST00000671881.1	c.635C>T	p.Pro212Leu	missense_variant	Exon 9 of 19		NM_015981.4	ENSP00000500386.1

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

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jul 12, 2024

Palindrome, Gene Kavoshgaran Aria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 03, 2017

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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
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;