Genetic Variant NUAK2:p.Arg596Gln (chr1-205303550-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.1787G>A(p.Arg596Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,510 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R596G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

NUAK2
NM_030952.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.301

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=0.026964307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUAK2	NM_030952.3 link	c.1787G>A	p.Arg596Gln	missense_variant	Exon 7 of 7	ENST00000367157.6	NP_112214.3	Q9H093B4E0Y5
NUAK2	XM_047431309.1 link	c.1391G>A	p.Arg464Gln	missense_variant	Exon 6 of 6		XP_047287265.1
NUAK2	XM_005245515.5 link	c.1046G>A	p.Arg349Gln	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.1787G>A	p.Arg596Gln	missense_variant	Exon 7 of 7	1	NM_030952.3	ENSP00000356125.5		Q9H093

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000719

AC:

AN:

250472

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461300

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726950

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.000640

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1787G>A (p.R596Q) 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 1787, causing the arginine (R) at amino acid position 596 to be replaced by a glutamine (Q). 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

0.066

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.72

M_CAP

Benign

0.017

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.27

REVEL

Benign

0.084

Sift4G

Benign

0.37

Vest4

0.11

MVP

0.59

MPC

0.31

ClinPred

0.027

GERP RS

3.1

gMVP

0.18

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