7-44241702-T-C

Variant names:

• chr7-44241702-T-C
• rs1554385111
• NM_001220.5:c.901A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K301K) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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]

CAMK2B Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 40

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• intellectual disability, autosomal dominant 54

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 430925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001220.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2B	NM_001220.5	MANE Select	c.901A>G	p.Lys301Glu	missense splice_region	Exon 11 of 24	NP_001211.3
	CAMK2B	NM_001293170.2		c.901A>G	p.Lys301Glu	missense splice_region	Exon 11 of 21	NP_001280099.1
	CAMK2B	NM_172078.3		c.901A>G	p.Lys301Glu	missense splice_region	Exon 11 of 21	NP_742075.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2B	ENST00000395749.7	TSL:1 MANE Select	c.901A>G	p.Lys301Glu	missense splice_region	Exon 11 of 24	ENSP00000379098.2
	CAMK2B	ENST00000440254.6	TSL:1	c.901A>G	p.Lys301Glu	missense splice_region	Exon 11 of 21	ENSP00000397937.2
	CAMK2B	ENST00000395747.6	TSL:1	c.901A>G	p.Lys301Glu	missense splice_region	Exon 11 of 19	ENSP00000379096.2

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

Nov 07, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Feb 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 28, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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 v4.9

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
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.091	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.80
MutPred		0.75		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554385111; hg19: chr7-44281301;