rs1554389088

chr7-44243526-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_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. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P139P) has been classified as Likely benign.

• 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:14
• Conservation: PhyloP100: 9.91

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 Pathogenic. Variant got 13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CAMK2B
• 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/exons	MANE	UniProt
CAMK2B	NM_001220.5	c.416C>T	p.Pro139Leu	missense_variant, splice_region_variant	7/24	ENST00000395749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK2B	ENST00000395749.7	c.416C>T	p.Pro139Leu	missense_variant, splice_region_variant	7/24	1	NM_001220.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461274 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 54 Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 22, 2024	Criteria applied: PS4, PS2_VSTR, PS3_MOD, PM2_SUP, PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Sep 11, 2017	This variant has been reported in PMID:29100089 (individual 20). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 21, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Gene Discovery Core-Manton Center, Boston Children's Hospital	Feb 05, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2022	ClinVar contains an entry for this variant (Variation ID: 430922). 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. This variant is not present in population databases (gnomAD no frequency). 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). 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAMK2B function (PMID: 29100089). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2017

- -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Apnea;C0013421:Dystonic disorder;C0020578:Hyperventilation;C0085631:Agitation;C0557874:Global developmental delay;C4551563:Microcephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Jul 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	34
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
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	D
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

Other links and lift over

dbSNP: rs1554389088; hg19: chr7-44283125;