rs1554389088

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001220.5(CAMK2B):c.416C>T(p.Pro139Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAMK2B
NM_001220.5 missense, splice_region

Scores

Splicing: ADA: 0.8697

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 7-44243526-G-A is Pathogenic according to our data. Variant chr7-44243526-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44243526-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMK2B	NM_001220.5 link	c.416C>T	p.Pro139Leu	missense_variant, splice_region_variant	Exon 7 of 24	ENST00000395749.7	NP_001211.3	Q13554-1A4D2J9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK2B	ENST00000395749.7 link	c.416C>T	p.Pro139Leu	missense_variant, splice_region_variant	Exon 7 of 24	1	NM_001220.5	ENSP00000379098.2		Q13554-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727006

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 54

Pathogenic:9

Jan 22, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4, PS2_VSTR, PS3_MOD, PM2_SUP, PP2 -

Apr 28, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 05, 2019

Gene Discovery Core-Manton Center, Boston Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been observed in at least two similarly affected unrelated individuals (PMID: 29100089, PS4_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29100089, , PS2_S). . Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.P139L in CAMK2B (NM_001220.4) hasbeen previously reported in an affected patient (Kury et al,2017). It has been classified as Likely Pathogenic in the ClinVar database. The p.P139L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P139L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 139 of CAMK2B is conserved in all mammalian species. The nucleotide c.416 in CAMK2B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Feb 14, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29100089) - PS3_moderate. The c.416C>T;p.(Pro139Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 430922; PMID: 32875707; 29100089) - PS4. This variant is not present in population databases (rs1554389088, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32875707; 29100089) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. -

Feb 21, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in PMID:29100089 (individual 20). -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PS2_VeryStrong+PS3_Moderate -

not provided

Pathogenic:3

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 139 of the CAMK2B protein (p.Pro139Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CAMK2B-related conditions (PMID: 29100089, 30842224, 31036916). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430922). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CAMK2B function (PMID: 29100089). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAMK2B: PS2:Very Strong, PM2, PP2 -

Oct 21, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (impairment of neuronal migration in murine models) (Kury et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 29100089, 30842224, 29100083, 30577886, 31036916, 30979967, 32875707, 31785789) -

Inborn genetic diseases

Pathogenic:1

Oct 12, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apnea;C0013421:Dystonic disorder;C0020578:Hyperventilation;C0085631:Agitation;C0557874:Global developmental delay;C4551563:Microcephaly

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Intellectual disability

Pathogenic:1

Jul 03, 2017

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.6

L;L;L;L;L;L;L;L;L;L;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.6

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.89

MutPred

0.86

Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);Gain of stability (P = 0.05);.;.;

MVP

0.62

MPC

2.8

ClinPred

1.0

GERP RS

4.1

Varity_R

0.83

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Pathogenic

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over