Genetic Variant NM_001220.5:c.328G>A (chr7-44254555-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.08

Publications

1 publications found

Variant links:

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

CAMK2B links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 54 (2)

Intellectual disability (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.7

PhyloP100

7.1

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.88

MutPred

0.86

Gain of ubiquitination at E110 (P = 0.0162)

MVP

0.68

MPC

3.0

ClinPred

1.0

GERP RS

3.6

Varity_R

0.87

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over