chr7-44220094-A-C

Variant names:

• chr7-44220094-A-C
• NM_001220.5:c.1969T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001220.5(CAMK2B):​c.1969T>G​(p.Cys657Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CAMK2B NM_001220.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38940984).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2B	NM_001220.5	MANE Select	c.1969T>G	p.Cys657Gly	missense	Exon 23 of 24	NP_001211.3
	CAMK2B	NM_001293170.2		c.1597T>G	p.Cys533Gly	missense	Exon 20 of 21	NP_001280099.1	Q13554-2
	CAMK2B	NM_172078.3		c.1597T>G	p.Cys533Gly	missense	Exon 20 of 21	NP_742075.1	Q13554-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2B	ENST00000395749.7	TSL:1 MANE Select	c.1969T>G	p.Cys657Gly	missense	Exon 23 of 24	ENSP00000379098.2	Q13554-1
	CAMK2B	ENST00000440254.6	TSL:1	c.1597T>G	p.Cys533Gly	missense	Exon 20 of 21	ENSP00000397937.2	Q13554-2
	CAMK2B	ENST00000395747.6	TSL:1	c.1525T>G	p.Cys509Gly	missense	Exon 19 of 19	ENSP00000379096.2	Q13554-5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal dominant 54 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Benign	0.93
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.88	P
Vest4		0.37
MutPred		0.51		Gain of disorder (P = 0.0358)
MVP		0.66
MPC		1.7
ClinPred		0.59	D
GERP RS		4.3
Varity_R		0.50
gMVP		0.94
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

hg19: chr7-44259693;