5-150252032-T-A

Variant names:

• chr5-150252032-T-A
• rs1554122129
• NM_015981.4:c.548A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 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
• Publications: 6 publications found

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]

CAMK2A Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 53

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 63

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 430914.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015981.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2A	NM_015981.4	MANE Select	c.548A>T	p.Glu183Val	missense	Exon 8 of 19	NP_057065.2
	CAMK2A	NM_001363989.1		c.548A>T	p.Glu183Val	missense	Exon 9 of 20	NP_001350918.1
	CAMK2A	NM_001363990.1		c.548A>T	p.Glu183Val	missense	Exon 9 of 19	NP_001350919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2A	ENST00000671881.1	MANE Select	c.548A>T	p.Glu183Val	missense	Exon 8 of 19	ENSP00000500386.1
	CAMK2A	ENST00000348628.11	TSL:1	c.548A>T	p.Glu183Val	missense	Exon 8 of 18	ENSP00000261793.8
	CAMK2A	ENST00000398376.8	TSL:1	c.548A>T	p.Glu183Val	missense	Exon 8 of 16	ENSP00000381412.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 53 Pathogenic:1

Apr 07, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Intellectual disability Pathogenic:1

Jul 03, 2017

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 v4.9

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
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.85		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
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs1554122129; hg19: chr5-149631595;