rs1554386687

chr7-44242328-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_001220.5(CAMK2B):c.709G>A(p.Glu237Lys) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2B NM_001220.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.82

Genes affected

CAMK2B (HGNC:1461): (calcium/calmodulin dependent protein kinase II beta) 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 beta chain. It is possible that distinct isoforms of this chain have different cellular localizations and interact differently with calmodulin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CAMK2B
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 7-44242328-C-T is Pathogenic according to our data. Variant chr7-44242328-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 430923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-44242328-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK2B	NM_001220.5	c.709G>A	p.Glu237Lys	missense_variant	10/24	ENST00000395749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK2B	ENST00000395749.7	c.709G>A	p.Glu237Lys	missense_variant	10/24	1	NM_001220.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAMK2B function (PMID: 29100089). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 430923). This missense change has been observed in individual(s) with CAMK2B-related conditions (PMID: 29100089). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 237 of the CAMK2B protein (p.Glu237Lys). -

Intellectual disability, autosomal dominant 54 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 08, 2017

- -

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	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;D;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.78
MutPred		0.66		Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);Gain of methylation at E237 (P = 0.0017);
MVP		0.69
MPC		2.8
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.86
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1554386687; hg19: chr7-44281927; COSMIC: COSV51661795; COSMIC: COSV51661795;