Genetic Variant NRK:p.Gly281Arg (chrX-105905339-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_198465.4(NRK):c.841G>A(p.Gly281Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000087 in 1,171,999 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000092 ( 0 hom. 31 hem. )

Consequence

NRK
NM_198465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15

Variant links:

Genes affected

NRK (HGNC:25391): (Nik related kinase) The mouse ortholog of this gene encodes a protein kinase required for JNK activation. The encoded protein may be involved in the induction of actin polymerization in late embryogenesis.[provided by RefSeq, Jun 2010]

NRK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21746448).

BS2

High Hemizygotes in GnomAdExome4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRK	NM_198465.4 link	c.841G>A	p.Gly281Arg	missense_variant	Exon 10 of 29	ENST00000243300.14	NP_940867.2	Q7Z2Y5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRK	ENST00000243300.14 link	c.841G>A	p.Gly281Arg	missense_variant	Exon 10 of 29	1	NM_198465.4	ENSP00000434830.1		Q7Z2Y5-1
NRK	ENST00000428173.3 link	n.841G>A		non_coding_transcript_exon_variant	Exon 10 of 23	2		ENSP00000438378.2		F5H049

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112083

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34295

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000158

AC:

AN:

170565

Hom.:

AF XY:

0.000138

AC XY:

AN XY:

57893

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000655

Gnomad NFE exome

AF:

0.000333

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.0000925

AC:

AN:

1059916

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

328640

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000105

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000191

Gnomad4 FIN exome

AF:

0.000124

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112083

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34295

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000752

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000157

AC:

ExAC

AF:

0.000307

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841G>A (p.G281R) alteration is located in exon 10 (coding exon 10) of the NRK gene. This alteration results from a G to A substitution at nucleotide position 841, causing the glycine (G) at amino acid position 281 to be replaced by an arginine (R). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.086

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.060

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.34

REVEL

Benign

0.28

Sift

Benign

0.039

Sift4G

Benign

0.26

Polyphen

1.0

Vest4

0.20

MutPred

0.47

Gain of MoRF binding (P = 0.0106);

MVP

0.68

ClinPred

0.16

GERP RS

5.0

Varity_R

0.11

gMVP

0.65

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