Variant 12-121253338-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001270485.2(CAMKK2):c.1042G>T(p.Val348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CAMKK2
NM_001270485.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.194244).

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMKK2	NM_001270485.2 linkuse as main transcript	c.1042G>T	p.Val348Leu	missense_variant	10/17	ENST00000404169.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMKK2	ENST00000404169.8 linkuse as main transcript	c.1042G>T	p.Val348Leu	missense_variant	10/17	1	NM_001270485.2	P3	Q96RR4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251470

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

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:

0.0000150

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000470

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:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000132

AC:

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

May 06, 2022

The c.1042G>T (p.V348L) alteration is located in exon 10 (coding exon 9) of the CAMKK2 gene. This alteration results from a G to T substitution at nucleotide position 1042, causing the valine (V) at amino acid position 348 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

Pathogenic

0.74

BayesDel_addAF

Benign

-0.089

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

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.084

MetaRNN

Benign

0.19

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

MutationTaster

Benign

1.0

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

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

0.24

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

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