12-121274156-G-A
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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
NM_001270485.2 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 8.81
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]
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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 |
---|---|---|---|---|---|---|---|
CAMKK2 | NM_001270485.2 | c.371C>T | p.Pro124Leu | missense_variant | 2/17 | ENST00000404169.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAMKK2 | ENST00000404169.8 | c.371C>T | p.Pro124Leu | missense_variant | 2/17 | 1 | NM_001270485.2 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000902 AC: 13AN: 1441886Hom.: 0 Cov.: 31 AF XY: 0.00000840 AC XY: 6AN XY: 714514
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
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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 13, 2022 | The 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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;D;.;D;D;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.;.;D;.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;L;L;L;L;L;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D;D;D;.
Vest4
MutPred
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
MPC
0.73
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at