12-121240724-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_001270485.2(CAMKK2):c.1742C>T(p.Pro581Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,606,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CAMKK2 NM_001270485.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.304

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0745177).
• BP6: Variant 12-121240724-G-A is Benign according to our data. Variant chr12-121240724-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2620522.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMKK2	NM_001270485.2	c.1742C>T	p.Pro581Leu	missense_variant	17/17	ENST00000404169.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMKK2	ENST00000404169.8	c.1742C>T	p.Pro581Leu	missense_variant	17/17	1	NM_001270485.2	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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

GnomAD3 exomes AF: 0.0000172 AC: 4 AN: 232888 Hom.: 0 AF XY: 0.0000233 AC XY: 3 AN XY: 128844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1454634 Hom.: 0 Cov.: 36 AF XY: 0.0000193 AC XY: 14 AN XY: 723934

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000583

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	6.7
Dann	Benign	0.86
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.58	T;.;.;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.075	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.38	N;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.057	T;T;T;.
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.066	B;B;B;B
Vest4		0.12
MutPred		0.28		.;Gain of catalytic residue at L579 (P = 0.0367);Gain of catalytic residue at L579 (P = 0.0367);Gain of catalytic residue at L579 (P = 0.0367);
MVP		0.71
MPC		0.38
ClinPred		0.035	T
GERP RS		2.2
Varity_R		0.027
gMVP		0.21

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: rs752954809; hg19: chr12-121678527;