12-121255566-G-A

Variant names:

• chr12-121255566-G-A
• rs139606987
• NM_001270485.2:c.891C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001270485.2(CAMKK2):​c.891C>T​(p.Ile297Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,611,374 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: CAMKK2 NM_001270485.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.66
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 12-121255566-G-A is Benign according to our data. Variant chr12-121255566-G-A is described in ClinVar as Benign. ClinVar VariationId is 771186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.66 with no splicing effect.
• BS2: High AC in GnomAd4 at 158 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.891C>T	p.Ile297Ile	synonymous	Exon 9 of 17	NP_001257414.1	Q96RR4-1
	CAMKK2	NM_006549.4		c.891C>T	p.Ile297Ile	synonymous	Exon 9 of 17	NP_006540.3
	CAMKK2	NM_001270486.1		c.891C>T	p.Ile297Ile	synonymous	Exon 8 of 16	NP_001257415.1	Q96RR4-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMKK2	ENST00000404169.8	TSL:1 MANE Select	c.891C>T	p.Ile297Ile	synonymous	Exon 9 of 17	ENSP00000384600.3	Q96RR4-1
	CAMKK2	ENST00000324774.9	TSL:1	c.891C>T	p.Ile297Ile	synonymous	Exon 9 of 17	ENSP00000312741.5	Q96RR4-1
	CAMKK2	ENST00000402834.8	TSL:1	c.891C>T	p.Ile297Ile	synonymous	Exon 9 of 17	ENSP00000384591.4	Q96RR4-1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 150966 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00174

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00241

GnomAD2 exomes AF: 0.00145 AC: 360 AN: 248752 AF XY: 0.00152

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00135 AC: 1971 AN: 1460290 Hom.: 4 Cov.: 30 AF XY: 0.00140 AC XY: 1015 AN XY: 726236

African (AFR) AF: 0.000179 AC: 6 AN: 33466

American (AMR) AF: 0.00173 AC: 77 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000735 AC: 63 AN: 85752

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53350

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5764

European-Non Finnish (NFE) AF: 0.00141 AC: 1569 AN: 1111338

Other (OTH) AF: 0.00224 AC: 135 AN: 60356

GnomAD4 genome AF: 0.00105 AC: 158 AN: 151084 Hom.: 0 Cov.: 29 AF XY: 0.000868 AC XY: 64 AN XY: 73742

African (AFR) AF: 0.000243 AC: 10 AN: 41134

American (AMR) AF: 0.00174 AC: 26 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10416

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 67924

Other (OTH) AF: 0.00239 AC: 5 AN: 2094

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00134

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		1.7
Mutation Taster		=89/11	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: rs139606987; hg19: chr12-121693369; COSMIC: COSV61212616;