12-121255588-C-T

Position:

chr12-121255588-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001270485.2(CAMKK2):c.869G>A(p.Arg290His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

CAMKK2
NM_001270485.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

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:

CAMKK2 (HGNC:):

CAMKK2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMKK2	NM_001270485.2 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	9/17	ENST00000404169.8	NP_001257414.1	Q96RR4-1A0A024RBQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMKK2	ENST00000404169.8 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	9/17	1	NM_001270485.2	ENSP00000384600.3		Q96RR4-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250038

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000989

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461112

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73746

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.869G>A (p.R290H) alteration is located in exon 9 (coding exon 8) of the CAMKK2 gene. This alteration results from a G to A substitution at nucleotide position 869, causing the arginine (R) at amino acid position 290 to be replaced by a histidine (H). 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

0.29

BayesDel_addAF

Benign

-0.0066

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

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

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

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

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.3

M;M;M;M;M;.;M;M;M;M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.24

Sift

Uncertain

0.015

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

Sift4G

Benign

0.19

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

Polyphen

0.97

D;D;P;D;D;P;D;D;D;D;D

Vest4

0.92

MutPred

0.77

Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);.;Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);Gain of catalytic residue at Q294 (P = 0.0038);

MVP

0.59

MPC

1.1

ClinPred

0.95

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over