NM_001321571.2:c.416C>T

Variant names:

• chr4-113537442-G-A
• NM_001321571.2:c.416C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001321571.2(CAMK2D):​c.416C>T​(p.Pro139Leu) variant causes a missense, splice region 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. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAMK2D NM_001321571.2 missense, splice_region
• Scores: Splicing: ADA: 0.9871
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.99
• 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: 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 4-113537442-G-A is Pathogenic according to our data. Variant chr4-113537442-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1343376.Status of the report is no_assertion_criteria_provided, 0 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.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 21	NP_001308500.1	E9PF82
	CAMK2D	NM_001321578.2		c.-173C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 18	NP_001308507.1
	CAMK2D	NM_001321585.2		c.-173C>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 20	NP_001308514.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2D	ENST00000511664.6	TSL:2 MANE Select	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 21	ENSP00000425824.1	E9PF82
	CAMK2D	ENST00000394522.7	TSL:1	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 18	ENSP00000378030.3	Q13557-10
	CAMK2D	ENST00000508738.5	TSL:1	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 18	ENSP00000422566.1	Q13557-9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	L
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.85		Gain of stability (P = 0.05)
MVP		0.84
MPC		2.4
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.66
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.14		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: chr4-114458598;