Genetic Variant NRK:p.Pro396Ser (chrX-105908827-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_198465.4(NRK):c.1186C>T(p.Pro396Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000091 in 1,208,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 4 hem. )

Consequence

NRK
NM_198465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40877652).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRK	NM_198465.4 link	c.1186C>T	p.Pro396Ser	missense_variant	Exon 13 of 29	ENST00000243300.14	NP_940867.2	Q7Z2Y5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NRK	ENST00000243300.14 link	c.1186C>T	p.Pro396Ser	missense_variant	Exon 13 of 29	1	NM_198465.4	ENSP00000434830.1	Q7Z2Y5-1
NRK	ENST00000428173.3 link	n.*1181C>T		non_coding_transcript_exon_variant	Exon 13 of 23	2		ENSP00000438378.2	F5H049
NRK	ENST00000428173.3 link	n.*1181C>T		3_prime_UTR_variant	Exon 13 of 23	2		ENSP00000438378.2	F5H049

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111577

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33755

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

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:

0.00000553

AC:

AN:

180769

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67053

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1096857

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362335

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000595

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111577

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33755

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000191

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:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1186C>T (p.P396S) alteration is located in exon 13 (coding exon 13) of the NRK gene. This alteration results from a C to T substitution at nucleotide position 1186, causing the proline (P) at amino acid position 396 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

0.25

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.41

MetaSVM

Uncertain

-0.055

MutationAssessor

Benign

0.81

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Benign

0.41

Polyphen

1.0

Vest4

0.23

MutPred

0.14

Gain of phosphorylation at P396 (P = 0.0146);

MVP

0.72

ClinPred

0.70

GERP RS

5.0

Varity_R

0.26

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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