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12-121274173-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001270485.2(CAMKK2):c.354C>T(p.Asn118=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,600,038 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0084 ( 19 hom., cov: 32)
Exomes 𝑓: 0.00095 ( 26 hom. )

Consequence

CAMKK2
NM_001270485.2 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.524
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.67).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-121274173-G-A is Benign according to our data. Variant chr12-121274173-G-A is described in ClinVar as [Benign]. Clinvar id is 709905.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.524 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00845 (1286/152194) while in subpopulation AFR AF= 0.0287 (1191/41522). AF 95% confidence interval is 0.0273. There are 19 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1282 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CAMKK2NM_001270485.2 linkuse as main transcriptc.354C>T p.Asn118= synonymous_variant 2/17 ENST00000404169.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CAMKK2ENST00000404169.8 linkuse as main transcriptc.354C>T p.Asn118= synonymous_variant 2/171 NM_001270485.2 P3Q96RR4-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00843
AC:
1282
AN:
152078
Hom.:
19
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0287
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00432
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.00239
AC:
559
AN:
233418
Hom.:
8
AF XY:
0.00172
AC XY:
218
AN XY:
127046
show subpopulations
Gnomad AFR exome
AF:
0.0291
Gnomad AMR exome
AF:
0.00234
Gnomad ASJ exome
AF:
0.00226
Gnomad EAS exome
AF:
0.0000569
Gnomad SAS exome
AF:
0.0000342
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000173
Gnomad OTH exome
AF:
0.00159
GnomAD4 exome
AF:
0.000954
AC:
1381
AN:
1447844
Hom.:
26
Cov.:
31
AF XY:
0.000830
AC XY:
596
AN XY:
718228
show subpopulations
Gnomad4 AFR exome
AF:
0.0293
Gnomad4 AMR exome
AF:
0.00249
Gnomad4 ASJ exome
AF:
0.00184
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000141
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000834
Gnomad4 OTH exome
AF:
0.00230
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00845
AC:
1286
AN:
152194
Hom.:
19
Cov.:
32
AF XY:
0.00836
AC XY:
622
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0287
Gnomad4 AMR
AF:
0.00432
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.00140
Hom.:
0
Bravo
AF:
0.00966
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeApr 20, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.67
Cadd
Benign
0.19
Dann
Benign
0.51

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs115336463; hg19: chr12-121711976; COSMIC: COSV61212725; COSMIC: COSV61212725; API