chr17-3876276-C-T

Position:

• chr17-3876276-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032294.3(CAMKK1):​c.943G>A​(p.Ala315Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAMKK1 NM_032294.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

Genes affected

CAMKK1 (HGNC:1469): (calcium/calmodulin dependent protein kinase kinase 1) The product of this gene belongs to the Serine/Threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. This protein plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade. Three transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMKK1	NM_032294.3	c.943G>A	p.Ala315Thr	missense_variant	10/16	ENST00000348335.7	NP_115670.1
CAMKK1	NM_172206.2	c.1024G>A	p.Ala342Thr	missense_variant	10/16		NP_757343.2
CAMKK1	NM_172207.3	c.1057G>A	p.Ala353Thr	missense_variant	11/16		NP_757344.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMKK1	ENST00000348335.7	c.943G>A	p.Ala315Thr	missense_variant	10/16	1	NM_032294.3	ENSP00000323118.3
CAMKK1	ENST00000381769.6	c.1024G>A	p.Ala342Thr	missense_variant	10/16	1		ENSP00000371188.2
CAMKK1	ENST00000158166.5	c.1057G>A	p.Ala353Thr	missense_variant	11/16	1		ENSP00000158166.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

The c.943G>A (p.A315T) alteration is located in exon 10 (coding exon 9) of the CAMKK1 gene. This alteration results from a G to A substitution at nucleotide position 943, causing the alanine (A) at amino acid position 315 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	.;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.76	.;N;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.86
MutPred		0.52		.;.;Gain of glycosylation at A353 (P = 0.0142);
MVP		0.86
MPC		1.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-3779570; COSMIC: COSV105029977; COSMIC: COSV105029977;