12-121240757-G-A

Position:

• chr12-121240757-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001270485.2(CAMKK2):​c.1709C>T​(p.Pro570Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 0.301

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09312731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMKK2	NM_001270485.2	c.1709C>T	p.Pro570Leu	missense_variant	17/17	ENST00000404169.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMKK2	ENST00000404169.8	c.1709C>T	p.Pro570Leu	missense_variant	17/17	1	NM_001270485.2	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.1709C>T (p.P570L) alteration is located in exon 17 (coding exon 16) of the CAMKK2 gene. This alteration results from a C to T substitution at nucleotide position 1709, causing the proline (P) at amino acid position 570 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.0040	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T;.;.;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.24	N;N;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.058	B;B;B;B
Vest4		0.17
MutPred		0.25		.;Gain of catalytic residue at W566 (P = 0);Gain of catalytic residue at W566 (P = 0);Gain of catalytic residue at W566 (P = 0);
MVP		0.83
MPC		0.38
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.068
gMVP		0.23

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: rs1888214396; hg19: chr12-121678560;