chr12-121253338-C-G

Variant names:

• chr12-121253338-C-G
• NM_001270485.2:c.1042G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001270485.2(CAMKK2):​c.1042G>C​(p.Val348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAMKK2 NM_001270485.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMKK2	NM_001270485.2	c.1042G>C	p.Val348Leu	missense_variant	Exon 10 of 17	ENST00000404169.8	NP_001257414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMKK2	ENST00000404169.8	c.1042G>C	p.Val348Leu	missense_variant	Exon 10 of 17	1	NM_001270485.2	ENSP00000384600.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;.;.;.;T;T;.;T;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;.;.;D;D;.;D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.96	L;L;L;L;L;.;L;L;L;L;L
PrimateAI	Uncertain	0.62	T
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		0.83	D
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121691141;