rs1554387293

Positions:

• chr7-44242618-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001220.5(CAMK2B):​c.638C>T​(p.Pro213Leu) 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:2
• Conservation: PhyloP100: 9.86

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAMK2B. . Gene score misZ 4.0707 (greater than the threshold 3.09). Trascript score misZ 3.3558 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 40, autosomal dominant non-syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 7-44242618-G-A is Pathogenic according to our data. Variant chr7-44242618-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 560179.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK2B	NM_001220.5	c.638C>T	p.Pro213Leu	missense_variant	9/24	ENST00000395749.7	NP_001211.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2B	ENST00000395749.7	c.638C>T	p.Pro213Leu	missense_variant	9/24	1	NM_001220.5	ENSP00000379098

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2022

Published functional studies demonstrate increased phosphorylation, and structural analysis suggested increased free energy change for the P213L variant (Akita et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29560374) -

Intellectual disability, autosomal dominant 54 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;.;T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.1	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.92
MutPred		0.78		Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);Gain of catalytic residue at P213 (P = 0.0083);
MVP		0.81
MPC		2.8
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.86
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554387293; hg19: chr7-44282217;