Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_015981.4(CAMK2A):c.704C>T(p.Pro235Leu) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

CAMK2A
NM_015981.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 10.0

Publications

4 publications found

Variant links:

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)

CAMK2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

PP5

Variant 5-150250800-G-A is Pathogenic according to our data. Variant chr5-150250800-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218729.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAMK2A	NM_015981.4	MANE Select	c.704C>T	p.Pro235Leu	missense	Exon 10 of 19	NP_057065.2
CAMK2A	NM_001363989.1		c.704C>T	p.Pro235Leu	missense	Exon 11 of 20	NP_001350918.1
CAMK2A	NM_001363990.1		c.704C>T	p.Pro235Leu	missense	Exon 11 of 19	NP_001350919.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAMK2A	ENST00000671881.1	MANE Select	c.704C>T	p.Pro235Leu	missense	Exon 10 of 19	ENSP00000500386.1
CAMK2A	ENST00000348628.11	TSL:1	c.704C>T	p.Pro235Leu	missense	Exon 10 of 18	ENSP00000261793.8
CAMK2A	ENST00000398376.8	TSL:1	c.704C>T	p.Pro235Leu	missense	Exon 10 of 16	ENSP00000381412.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 53 (2)

Intellectual disability (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

0.0075

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.3

PhyloP100

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-8.8

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.64

MutPred

0.64

Gain of catalytic residue at P235 (P = 0.0045)

MVP

0.80

MPC

2.9

ClinPred

1.0

GERP RS

4.3

Varity_R

0.83

gMVP

0.91

Mutation Taster

=41/59

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs864309606

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over