7-44220094-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMK2B	NM_001220.5	c.1969T>G	p.Cys657Gly	missense_variant	Exon 23 of 24	ENST00000395749.7	NP_001211.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK2B	ENST00000395749.7	c.1969T>G	p.Cys657Gly	missense_variant	Exon 23 of 24	1	NM_001220.5	ENSP00000379098.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 54 Uncertain:1

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1969T>Gp.Cys657Gly variant in CAMK2B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Cys657Gly variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Disease causing predict conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on CAMK2B gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 657 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.11	T;T;T;T;T;T;T;T;D;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.88	P;B;D;.;P;D;B;B;D;D;B
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44259693;