Variant 7-44220085-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001220.5(CAMK2B):c.1978G>T(p.Ala660Ser) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A660T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAMK2B
NM_001220.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAMK2B. . Gene score misZ 4.0707 (greater than the threshold 3.09). Trascript score misZ 3.3558 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 40, autosomal dominant non-syndromic intellectual disability.

BP4

Computational evidence support a benign effect (MetaRNN=0.2764059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK2B	NM_001220.5 linkuse as main transcript	c.1978G>T	p.Ala660Ser	missense_variant	23/24	ENST00000395749.7	NP_001211.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2B	ENST00000395749.7 linkuse as main transcript	c.1978G>T	p.Ala660Ser	missense_variant	23/24	1	NM_001220.5	ENSP00000379098		Q13554-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720264

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with CAMK2B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 660 of the CAMK2B protein (p.Ala660Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

.;.;T;.;.;.;.;.;.;.;.

Eigen

Benign

-0.013

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;.;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.28

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.19

.;.;N;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.90

D;D;D;D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.69

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.45

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.18

B;B;P;.;B;D;B;B;D;P;B

Vest4

0.46

MutPred

0.61

.;.;Gain of glycosylation at A660 (P = 0.0243);.;.;.;.;.;.;.;.;

MVP

0.51

MPC

1.6

ClinPred

0.88

GERP RS

4.3

Varity_R

0.12

gMVP

0.84

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over