rs1554385111

Positions:

• chr7-44241702-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001220.5(CAMK2B):​c.901A>G​(p.Lys301Glu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K301N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2B NM_001220.5 missense, splice_region
• Scores: Splicing: ADA: 0.07755
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.85

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-44241700-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 7-44241702-T-C is Pathogenic according to our data. Variant chr7-44241702-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44241702-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK2B	NM_001220.5	c.901A>G	p.Lys301Glu	missense_variant, splice_region_variant	11/24	ENST00000395749.7	NP_001211.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2B	ENST00000395749.7	c.901A>G	p.Lys301Glu	missense_variant, splice_region_variant	11/24	1	NM_001220.5	ENSP00000379098.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2024

Published functional studies demonstrate impaired neuronal migration when expressed in developing mouse brains, as well as reduced pT286/287 phosphorylation when expressed in HEK293T cells (PMID: 29100089); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29100089) -

Intellectual disability, autosomal dominant 54 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 28, 2022

- -

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	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.091	D
MutationAssessor	Pathogenic	2.9	M;M;M;M;M;M;M;M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;P;D;D;P;P;D;B;D;P
Vest4		0.80
MutPred		0.75		Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);Loss of methylation at K301 (P = 0.0467);
MVP		0.85
MPC		2.5
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.73
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.078
dbscSNV1_RF	Benign	0.36
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: rs1554385111; hg19: chr7-44281301;