Variant chr4-113517631-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001321571.2(CAMK2D):c.628G>A(p.Gly210Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAMK2D
NM_001321571.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

CAMK2D (HGNC:1462): (calcium/calmodulin dependent protein kinase II delta) 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 delta chain. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Distinct isoforms of this chain have different expression patterns.[provided by RefSeq, Nov 2008]

CAMK2D links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 4-113517631-C-T is Pathogenic according to our data. Variant chr4-113517631-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2442394.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK2D	NM_001321571.2 linkuse as main transcript	c.628G>A	p.Gly210Arg	missense_variant	9/21	ENST00000511664.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK2D	ENST00000511664.6 linkuse as main transcript	c.628G>A	p.Gly210Arg	missense_variant	9/21	2	NM_001321571.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1421812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709828

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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;in vivo;research

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

Feb 08, 2023

The p.(Gly210Arg) variant in CAMK2D is de novo, absent from large population studies and predicted pathogenic by most bioinformatics programs (CADD, REVEL, Metadome...). Besides, it affects the catalytic domain of CAMK2D, and is close to other variants identified in individuals with similar phenotype, and classified pathogenic. Additionally, in vitro functional studies indicate that the p.(Gly210Arg) variant increases phosphotransferase activity of CAMK2, and in vivo functional studies in mouse brain embryo showed that it causes severe migration deficit. In summary, the p.(Gly210Arg) variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

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

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

-0.031

MutationAssessor

Uncertain

2.4

M;M;.;M;M;.;M;.;M;M;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.1

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

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.93

MutPred

0.91

Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);Gain of catalytic residue at G210 (P = 0.0716);.;

MVP

0.69

MPC

2.6

ClinPred

1.0

GERP RS

5.4

Varity_R

0.95

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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