rs864309606

Variant names:

• chr5-150250800-G-A
• rs864309606
• NM_015981.4:c.704C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 10.0

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CAMK2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.6751 (above the threshold of 3.09). Trascript score misZ: 6.103 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.875
• 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 id is 218729.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMK2A	NM_015981.4	c.704C>T	p.Pro235Leu	missense_variant	Exon 10 of 19	ENST00000671881.1	NP_057065.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK2A	ENST00000671881.1	c.704C>T	p.Pro235Leu	missense_variant	Exon 10 of 19		NM_015981.4	ENSP00000500386.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 53 Pathogenic:2

Apr 07, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAMK2A c.704C>T (p.Pro235Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249322 control chromosomes. c.704C>T has been reported in the literature as de novo in individuals affected with Intellectual Disability, Autosomal Dominant 53 (Kury_2017, Akita_2018). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kury_2017, Akita_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29560374, 30577886, 29100089). ClinVar contains an entry for this variant (Variation ID: 218729). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

- -

not specified Uncertain:1

Jun 08, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.64		Gain of catalytic residue at P235 (P = 0.0045);Gain of catalytic residue at P235 (P = 0.0045);
MVP		0.80
MPC		2.9
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.83
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs864309606; hg19: chr5-149630363;