Genetic Variant NUAK2:p.Gly506Ser (chr1-205303821-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030952.3(NUAK2):c.1516G>A(p.Gly506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 1,598,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

NUAK2
NM_030952.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

Variant links:

Genes affected

NUAK2 (HGNC:29558): (NUAK family kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including cellular response to glucose starvation; negative regulation of apoptotic process; and protein phosphorylation. Predicted to be active in cytoplasm. Implicated in anencephaly. [provided by Alliance of Genome Resources, Apr 2022]

NUAK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020591885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUAK2	NM_030952.3 link	c.1516G>A	p.Gly506Ser	missense_variant	Exon 7 of 7	ENST00000367157.6	NP_112214.3	Q9H093B4E0Y5
NUAK2	XM_047431309.1 link	c.1120G>A	p.Gly374Ser	missense_variant	Exon 6 of 6		XP_047287265.1
NUAK2	XM_005245515.5 link	c.775G>A	p.Gly259Ser	missense_variant	Exon 3 of 3		XP_005245572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUAK2	ENST00000367157.6 link	c.1516G>A	p.Gly506Ser	missense_variant	Exon 7 of 7	1	NM_030952.3	ENSP00000356125.5		Q9H093

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.000478

GnomAD3 exomes

AF:

0.000151

AC:

AN:

238838

Hom.:

AF XY:

0.0000773

AC XY:

AN XY:

129332

show subpopulations

Gnomad AFR exome

AF:

0.00200

Gnomad AMR exome

AF:

0.0000623

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000697

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1446096

Hom.:

Cov.:

AF XY:

0.0000376

AC XY:

AN XY:

718348

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.000118

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000672

GnomAD4 genome

AF:

0.000473

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.000523

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:

0.000473

Alfa

AF:

0.0000920

Hom.:

Bravo

AF:

0.000563

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1516G>A (p.G506S) alteration is located in exon 7 (coding exon 7) of the NUAK2 gene. This alteration results from a G to A substitution at nucleotide position 1516, causing the glycine (G) at amino acid position 506 to be replaced by a serine (S). 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

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.75

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.022

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.65

PrimateAI

Uncertain

0.53

REVEL

Benign

0.21

Sift4G

Benign

0.41

Vest4

0.15

MVP

0.79

MPC

0.33

ClinPred

0.031

GERP RS

4.9

gMVP

0.25

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over