12-121274156-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001270485.2(CAMKK2):​c.371C>T​(p.Pro124Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,594,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

CAMKK2
NM_001270485.2 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.81
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.794
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CAMKK2NM_001270485.2 linkuse as main transcriptc.371C>T p.Pro124Leu missense_variant 2/17 ENST00000404169.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CAMKK2ENST00000404169.8 linkuse as main transcriptc.371C>T p.Pro124Leu missense_variant 2/171 NM_001270485.2 P3Q96RR4-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000902
AC:
13
AN:
1441886
Hom.:
0
Cov.:
31
AF XY:
0.00000840
AC XY:
6
AN XY:
714514
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000511
Gnomad4 SAS exome
AF:
0.0000356
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000727
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000285
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsMay 13, 2022The c.371C>T (p.P124L) alteration is located in exon 2 (coding exon 1) of the CAMKK2 gene. This alteration results from a C to T substitution at nucleotide position 371, causing the proline (P) at amino acid position 124 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
0.14
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
.;.;.;.;D;.;D;D;.;.;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D;D;D;.;.;D;.;D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.071
D
MutationAssessor
Benign
0.97
L;L;L;L;L;L;L;L;L;L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.1
D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D;D;D;.
Vest4
0.63
MutPred
0.36
Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);Gain of catalytic residue at P124 (P = 0);
MVP
0.82
MPC
0.73
ClinPred
0.98
D
GERP RS
5.1
Varity_R
0.40
gMVP
0.49

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.

Other links and lift over

dbSNP: rs199839826; hg19: chr12-121711959; API