chr4-113513852-A-G

Variant names:

• chr4-113513852-A-G
• NM_001321571.2:c.881T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001321571.2(CAMK2D):​c.881T>C​(p.Phe294Ser) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2D NM_001321571.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.26
• Publications: 0 publications found

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

ENSG00000308709 (HGNC:58873):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 4-113513852-A-G is Pathogenic according to our data. Variant chr4-113513852-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1343380.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321571.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2D	NM_001321571.2	MANE Select	c.881T>C	p.Phe294Ser	missense	Exon 11 of 21	NP_001308500.1	E9PF82
	CAMK2D	NM_001321569.2		c.881T>C	p.Phe294Ser	missense	Exon 11 of 21	NP_001308498.1
	CAMK2D	NM_001321573.2		c.881T>C	p.Phe294Ser	missense	Exon 11 of 21	NP_001308502.1	Q13557-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2D	ENST00000511664.6	TSL:2 MANE Select	c.881T>C	p.Phe294Ser	missense	Exon 11 of 21	ENSP00000425824.1	E9PF82
	CAMK2D	ENST00000394522.7	TSL:1	c.881T>C	p.Phe294Ser	missense	Exon 11 of 18	ENSP00000378030.3	Q13557-10
	CAMK2D	ENST00000508738.5	TSL:1	c.881T>C	p.Phe294Ser	missense	Exon 11 of 18	ENSP00000422566.1	Q13557-9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	CAMK2D-related condition (1)
1	-	-	Neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.94	P
Vest4		0.92
MutPred		0.69		Gain of disorder (P = 0.0039)
MVP		0.83
MPC		3.1
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

hg19: chr4-114435008;