chr7-44254555-C-T

Position:

• chr7-44254555-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001220.5(CAMK2B):​c.328G>A​(p.Glu110Lys) variant causes a missense change. 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: 30)
• Consequence: CAMK2B NM_001220.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.08

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 7-44254555-C-T is Pathogenic according to our data. Variant chr7-44254555-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 430921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44254555-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK2B	NM_001220.5	c.328G>A	p.Glu110Lys	missense_variant	5/24	ENST00000395749.7	NP_001211.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2B	ENST00000395749.7	c.328G>A	p.Glu110Lys	missense_variant	5/24	1	NM_001220.5	ENSP00000379098.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 54 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been previously reported as de novo in a similarly affected individual (PMID: 29100089, , PS2_S). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.996, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2022

Published functional studies demonstrate a damaging effect as in vitro assay showed E110K had reduced expression along with reduced pT286/287 phosphorylation (Kury et al., 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29100089, 35813072, 33774142, 35620293) -

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	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	.;.;T;.;.;.;.;.;.;.;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M;M;M;M;M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;.;.;.
Polyphen		1.0	D;D;D;D;P;D;D;P;P;D;.;.;.
Vest4		0.88
MutPred		0.86		Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);.;Gain of ubiquitination at E110 (P = 0.0162);Gain of ubiquitination at E110 (P = 0.0162);
MVP		0.68
MPC		3.0
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554402092; hg19: chr7-44294154; COSMIC: COSV99322935;