12-121274136-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001270485.2(CAMKK2):c.391G>A(p.Val131Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,429,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CAMKK2 NM_001270485.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069146514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMKK2	NM_001270485.2	c.391G>A	p.Val131Ile	missense_variant	2/17	ENST00000404169.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMKK2	ENST00000404169.8	c.391G>A	p.Val131Ile	missense_variant	2/17	1	NM_001270485.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000133 AC: 19 AN: 1429940 Hom.: 0 Cov.: 31 AF XY: 0.0000127 AC XY: 9 AN XY: 707440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000988

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.391G>A (p.V131I) alteration is located in exon 2 (coding exon 1) of the CAMKK2 gene. This alteration results from a G to A substitution at nucleotide position 391, causing the valine (V) at amino acid position 131 to be replaced by an isoleucine (I). 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	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.3
Dann	Benign	0.86
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.74	T;T;T;.;.;T;.;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.069	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;N;N;N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.24	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.25	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T
Polyphen		0.011	B;B;B;B;B;B;B;B;B;B
Vest4		0.093
MutPred		0.26		Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);Gain of catalytic residue at Y128 (P = 0);
MVP		0.43
MPC		0.30
ClinPred		0.034	T
GERP RS		4.2
Varity_R		0.017
gMVP		0.14

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

Other links and lift over

dbSNP: rs766586427; hg19: chr12-121711939;