chr7-44254555-C-T

Variant names:

• chr7-44254555-C-T
• rs1554402092
• NM_001220.5:c.328G>A

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.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
• 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 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 VariationId is 430921.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.328G>A	p.Glu110Lys	missense	Exon 5 of 24	NP_001211.3
	CAMK2B	NM_001293170.2		c.328G>A	p.Glu110Lys	missense	Exon 5 of 21	NP_001280099.1
	CAMK2B	NM_172078.3		c.328G>A	p.Glu110Lys	missense	Exon 5 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.328G>A	p.Glu110Lys	missense	Exon 5 of 24	ENSP00000379098.2
	CAMK2B	ENST00000440254.6	TSL:1	c.328G>A	p.Glu110Lys	missense	Exon 5 of 21	ENSP00000397937.2
	CAMK2B	ENST00000395747.6	TSL:1	c.328G>A	p.Glu110Lys	missense	Exon 5 of 19	ENSP00000379096.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.86		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554402092; hg19: chr7-44294154; COSMIC: COSV99322935;