Genetic Variant NM_001270485.2:c.1042G>C (chr12-121253338-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001270485.2(CAMKK2):c.1042G>C(p.Val348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CAMKK2
NM_001270485.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.84

Variant links:

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]

CAMKK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMKK2	NM_001270485.2 link	c.1042G>C	p.Val348Leu	missense_variant	Exon 10 of 17	ENST00000404169.8	NP_001257414.1	Q96RR4-1A0A024RBQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMKK2	ENST00000404169.8 link	c.1042G>C	p.Val348Leu	missense_variant	Exon 10 of 17	1	NM_001270485.2	ENSP00000384600.3		Q96RR4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;.;.;.;T;T;.;T;T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;.;.;D;D;.;D;D;D

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.96

L;L;L;L;L;.;L;L;L;L;L

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;N;.;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0060

D;T;D;D;D;D;D;D;.;T;D

Sift4G

Uncertain

0.010

D;D;D;D;D;T;D;D;D;D;D

Polyphen

0.87

P;D;B;P;P;B;P;P;P;P;P

Vest4

0.26

MutPred

0.76

Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);.;Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);Gain of catalytic residue at N346 (P = 0);

MVP

0.80

MPC

0.81

ClinPred

0.83

GERP RS

5.3

Varity_R

0.79

gMVP

0.45

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over