rs1554122129

Positions:

• chr5-150252032-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_015981.4(CAMK2A):​c.548A>T​(p.Glu183Val) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAMK2A NM_015981.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.02

Genes affected

CAMK2A (HGNC:1460): (calcium/calmodulin dependent protein kinase II alpha) The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2018]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAMK2A. . Gene score misZ 4.6751 (greater than the threshold 3.09). Trascript score misZ 6.103 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal recessive 63, intellectual disability, autosomal dominant 40, autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 53.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 5-150252032-T-A is Pathogenic according to our data. Variant chr5-150252032-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 430914.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-150252032-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK2A	NM_015981.4	c.548A>T	p.Glu183Val	missense_variant	8/19	ENST00000671881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK2A	ENST00000671881.1	c.548A>T	p.Glu183Val	missense_variant	8/19		NM_015981.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 53 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 07, 2022

- -

Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Jul 03, 2017

- -

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	35
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.85		Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);
MVP		0.94
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.89
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -3
DS_AL_spliceai		0.22		Position offset: 33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554122129; hg19: chr5-149631595;