12-121253327-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001270485.2(CAMKK2):c.1053C>T(p.Pro351=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,614,162 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (200 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (168 hom.)
• Consequence: CAMKK2 NM_001270485.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.52

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-121253327-G-A is Benign according to our data. Variant chr12-121253327-G-A is described in ClinVar as [Benign]. Clinvar id is 781092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMKK2	NM_001270485.2	c.1053C>T	p.Pro351=	synonymous_variant	10/17	ENST00000404169.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMKK2	ENST00000404169.8	c.1053C>T	p.Pro351=	synonymous_variant	10/17	1	NM_001270485.2	P3

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4147 AN: 152168 Hom.: 199 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00790 AC: 1987 AN: 251464 Hom.: 92 AF XY: 0.00592 AC XY: 805 AN XY: 135918

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00310 AC: 4539 AN: 1461876 Hom.: 168 Cov.: 33 AF XY: 0.00272 AC XY: 1975 AN XY: 727240

Gnomad4 AFR exome AF: 0.0946

Gnomad4 AMR exome AF: 0.00617

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000478

Gnomad4 OTH exome AF: 0.00666

GnomAD4 genome AF: 0.0273 AC: 4161 AN: 152286 Hom.: 200 Cov.: 32 AF XY: 0.0258 AC XY: 1918 AN XY: 74472

Gnomad4 AFR AF: 0.0942

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0116 Hom.: 37

Bravo AF: 0.0315

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.1
Dann	Benign	0.75

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

Other links and lift over

dbSNP: rs56131600; hg19: chr12-121691130;