Variant chr12-121250025-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001270485.2(CAMKK2):c.1171A>T(p.Met391Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAMKK2
NM_001270485.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.93

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:

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ACMG classification

Classification made for transcript

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=0.21854773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMKK2	NM_001270485.2 linkuse as main transcript	c.1171A>T	p.Met391Leu	missense_variant	12/17	ENST00000404169.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMKK2	ENST00000404169.8 linkuse as main transcript	c.1171A>T	p.Met391Leu	missense_variant	12/17	1	NM_001270485.2	P3	Q96RR4-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247628

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134034

show subpopulations

Gnomad AFR exome

AF:

0.0000636

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460442

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726422

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

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

Aug 02, 2021

The c.1171A>T (p.M391L) alteration is located in exon 12 (coding exon 11) of the CAMKK2 gene. This alteration results from a A to T substitution at nucleotide position 1171, causing the methionine (M) at amino acid position 391 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

0.17

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Benign

0.80

DEOGEN2

Benign

0.075

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

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.057

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.22

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.020

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.61

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

REVEL

Benign

0.17

Sift

Benign

0.80

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

Sift4G

Benign

0.71

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

Polyphen

0.0020

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.45

MutPred

0.49

Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);.;Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);Gain of catalytic residue at Q387 (P = 2e-04);

MVP

0.79

MPC

0.39

ClinPred

0.19

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.69

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