4-113513360-A-G

Position:

• chr4-113513360-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001321571.2(CAMK2D):​c.914T>C​(p.Leu305Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2D NM_001321571.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK2D	NM_001321571.2	c.914T>C	p.Leu305Ser	missense_variant	12/21	ENST00000511664.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK2D	ENST00000511664.6	c.914T>C	p.Leu305Ser	missense_variant	12/21	2	NM_001321571.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	.;.;T;D;.;T;.;T;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T;T;D;T;D;D;T;D;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Uncertain	2.8	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	0.92	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.023	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.074	T;T;T;D;T;T;T;T;T;T;.
Polyphen		0.81	P;.;D;P;D;.;.;.;.;.;.
Vest4		0.96
MutPred		0.64		Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);.;
MVP		0.96
MPC		2.0
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs1590480879; hg19: chr4-114434516;