Genetic Variant NM_001270485.2:c.891C>A (chr12-121255566-G-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_001270485.2(CAMKK2):c.891C>A(p.Ile297Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I297I) has been classified as Benign.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAMKK2
NM_001270485.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

Publications

0 publications found

Variant links:

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]

CAMKK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP7

Synonymous conserved (PhyloP=1.66 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAMKK2	NM_001270485.2	MANE Select	c.891C>A	p.Ile297Ile	synonymous	Exon 9 of 17	NP_001257414.1	Q96RR4-1
CAMKK2	NM_006549.4		c.891C>A	p.Ile297Ile	synonymous	Exon 9 of 17	NP_006540.3
CAMKK2	NM_001270486.1		c.891C>A	p.Ile297Ile	synonymous	Exon 8 of 16	NP_001257415.1	Q96RR4-7

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460294

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726240

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

85750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111344

Other (OTH)

AF:

0.0000166

AC:

AN:

60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over