chr12-121248655-T-G

Variant names:

• chr12-121248655-T-G
• NM_001270485.2:c.1403A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001270485.2(CAMKK2):​c.1403A>C​(p.Glu468Ala) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMKK2 NM_001270485.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

Genes affected

CAMKK2 (HGNC:1470): (calcium/calmodulin dependent protein kinase kinase 2) The product of this gene belongs to the Serine/Threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. The major isoform of this gene plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4. Protein products of this gene also phosphorylate AMP-activated protein kinase (AMPK). This gene has its strongest expression in the brain and influences signalling cascades involved with learning and memory, neuronal differentiation and migration, neurite outgrowth, and synapse formation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. The identified isoforms differ in their ability to undergo autophosphorylation and to phosphorylate downstream kinases. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270485.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMKK2	NM_001270485.2	MANE Select	c.1403A>C	p.Glu468Ala	missense	Exon 14 of 17	NP_001257414.1	Q96RR4-1
	CAMKK2	NM_006549.4		c.1403A>C	p.Glu468Ala	missense	Exon 14 of 17	NP_006540.3
	CAMKK2	NM_001270486.1		c.1403A>C	p.Glu468Ala	missense	Exon 13 of 16	NP_001257415.1	Q96RR4-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMKK2	ENST00000404169.8	TSL:1 MANE Select	c.1403A>C	p.Glu468Ala	missense	Exon 14 of 17	ENSP00000384600.3	Q96RR4-1
	CAMKK2	ENST00000324774.9	TSL:1	c.1403A>C	p.Glu468Ala	missense	Exon 14 of 17	ENSP00000312741.5	Q96RR4-1
	CAMKK2	ENST00000402834.8	TSL:1	c.1403A>C	p.Glu468Ala	missense	Exon 14 of 17	ENSP00000384591.4	Q96RR4-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.032	D
Polyphen		0.96	D
Vest4		0.70
MutPred		0.42		Loss of disorder (P = 0.0327)
MVP		0.56
MPC		0.53
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.65
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr12-121686458;