NM_015981.4:c.856A>C

Variant names:

• chr5-150250270-T-G
• rs1554121872
• NM_015981.4:c.856A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_015981.4(CAMK2A):​c.856A>C​(p.Thr286Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T286N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2A NM_015981.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.02
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150250269-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2662703.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 5-150250270-T-G is Pathogenic according to our data. Variant chr5-150250270-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 430918.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.856A>C	p.Thr286Pro	missense	Exon 11 of 19	NP_057065.2
	CAMK2A	NM_001363989.1		c.856A>C	p.Thr286Pro	missense	Exon 12 of 20	NP_001350918.1
	CAMK2A	NM_001363990.1		c.856A>C	p.Thr286Pro	missense	Exon 12 of 19	NP_001350919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2A	ENST00000671881.1	MANE Select	c.856A>C	p.Thr286Pro	missense	Exon 11 of 19	ENSP00000500386.1
	CAMK2A	ENST00000348628.11	TSL:1	c.856A>C	p.Thr286Pro	missense	Exon 11 of 18	ENSP00000261793.8
	CAMK2A	ENST00000398376.8	TSL:1	c.856A>C	p.Thr286Pro	missense	Exon 11 of 16	ENSP00000381412.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.59		Loss of MoRF binding (P = 0.0621)
MVP		0.81
MPC		3.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

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

dbSNP: rs1554121872; hg19: chr5-149629833;