NM_001220.5:c.709G>A

Variant names:

• chr7-44242328-C-T
• rs1554386687
• NM_001220.5:c.709G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

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, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.82
• Publications: 1 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 430923.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.709G>A	p.Glu237Lys	missense	Exon 10 of 24	NP_001211.3
	CAMK2B	NM_001293170.2		c.709G>A	p.Glu237Lys	missense	Exon 10 of 21	NP_001280099.1
	CAMK2B	NM_172078.3		c.709G>A	p.Glu237Lys	missense	Exon 10 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.709G>A	p.Glu237Lys	missense	Exon 10 of 24	ENSP00000379098.2
	CAMK2B	ENST00000440254.6	TSL:1	c.709G>A	p.Glu237Lys	missense	Exon 10 of 21	ENSP00000397937.2
	CAMK2B	ENST00000395747.6	TSL:1	c.709G>A	p.Glu237Lys	missense	Exon 10 of 19	ENSP00000379096.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Intellectual disability (1)
1	-	-	Intellectual disability, autosomal dominant 54 (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.66		Gain of methylation at E237 (P = 0.0017)
MVP		0.69
MPC		2.8
ClinPred		0.98	D
GERP RS		4.4
PromoterAI		-0.016	Neutral
Varity_R		0.86
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554386687; hg19: chr7-44281927; COSMIC: COSV51661795; COSMIC: COSV51661795;