4-113513909-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP5_Moderate

The NM_001321571.2(CAMK2D):c.824G>A(p.Arg275His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

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:2

Conservation

PhyloP100: 7.83

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

CAMK2D-related neurodevelopmental disorder and dilated cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: G2P
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

CAMK2D links:

ENSG00000308709 (HGNC:):

ENSG00000308709 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.1055 (above the threshold of 3.09). Trascript score misZ: 1.1706 (below the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, CAMK2D-related neurodevelopmental disorder and dilated cardiomyopathy.

PP5

Variant 4-113513909-C-T is Pathogenic according to our data. Variant chr4-113513909-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1343378.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMK2D	NM_001321571.2 link	c.824G>A	p.Arg275His	missense_variant	Exon 11 of 21	ENST00000511664.6	NP_001308500.1	E9PF82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK2D	ENST00000511664.6 link	c.824G>A	p.Arg275His	missense_variant	Exon 11 of 21	2	NM_001321571.2	ENSP00000425824.1		E9PF82

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1380630

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690748

African (AFR)

AF:

0.00

AC:

AN:

31140

American (AMR)

AF:

0.00

AC:

AN:

41202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25090

East Asian (EAS)

AF:

0.00

AC:

AN:

39084

South Asian (SAS)

AF:

0.00

AC:

AN:

81758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046244

Other (OTH)

AF:

0.00

AC:

AN:

57400

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 01, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Segregates with disease in affected individuals from at least one family referred for genetic testing at GeneDx and in published literature (PMID: 38272033); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate an increase in protein expression (PMID: 38272033); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 37372357, 38272033) -

Neurodevelopmental disorder

Pathogenic:1

Mar 07, 2022

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

0.90

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

.;.;T;D;.;T;.;T;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.63

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

MetaSVM

Benign

-0.42

MutationAssessor

Benign

2.0

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

PhyloP100

7.8

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.3

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

REVEL

Uncertain

0.30

Sift

Uncertain

0.028

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

Sift4G

Benign

0.11

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

Polyphen

0.082

B;.;B;B;B;.;.;.;.;.;.

Vest4

0.62

MutPred

0.60

Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);.;

MVP

0.76

MPC

1.4

ClinPred

0.98

GERP RS

5.1

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.74

gMVP

0.84

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over