rs201638594

Variant names:

• chr12-121240713-T-C
• rs201638594
• NM_001270485.2:c.1753A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001270485.2(CAMKK2):​c.1753A>G​(p.Met585Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,604,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: CAMKK2 NM_001270485.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.794
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058300585).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270485.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMKK2	NM_001270485.2	MANE Select	c.1753A>G	p.Met585Val	missense	Exon 17 of 17	NP_001257414.1	Q96RR4-1
	CAMKK2	NM_006549.4		c.1753A>G	p.Met585Val	missense	Exon 17 of 17	NP_006540.3
	CAMKK2	NM_172216.2		c.1624A>G	p.Met542Val	missense	Exon 16 of 16	NP_757365.1	Q96RR4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMKK2	ENST00000404169.8	TSL:1 MANE Select	c.1753A>G	p.Met585Val	missense	Exon 17 of 17	ENSP00000384600.3	Q96RR4-1
	CAMKK2	ENST00000324774.9	TSL:1	c.1753A>G	p.Met585Val	missense	Exon 17 of 17	ENSP00000312741.5	Q96RR4-1
	CAMKK2	ENST00000402834.8	TSL:1	c.1753A>G	p.Met585Val	missense	Exon 17 of 17	ENSP00000384591.4	Q96RR4-1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000955 AC: 22 AN: 230316 AF XY: 0.0000707

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00157

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000289

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.0000454 AC: 66 AN: 1452712 Hom.: 0 Cov.: 36 AF XY: 0.0000526 AC XY: 38 AN XY: 722864

African (AFR) AF: 0.00 AC: 0 AN: 33218

American (AMR) AF: 0.00 AC: 0 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 41 AN: 25900

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39576

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110116

Other (OTH) AF: 0.000217 AC: 13 AN: 60040

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000498 AC: 6

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.79
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.55
MVP		0.95
MPC		0.38
ClinPred		0.058	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.30
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs201638594; hg19: chr12-121678516;