Genetic Variant NRK:p.Gln355His (chrX-105908283-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198465.4(NRK):c.1065G>C(p.Gln355His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,078,471 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., 15 hem., cov: 23)

Exomes 𝑓: 0.000033 ( 0 hom. 5 hem. )

Consequence

NRK
NM_198465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.508

Publications

2 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008197695).

BS2

High Hemizygotes in GnomAd4 at 15 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRK	NM_198465.4	MANE Select	c.1065G>C	p.Gln355His	missense	Exon 12 of 29	NP_940867.2	Q7Z2Y5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRK	ENST00000243300.14	TSL:1 MANE Select	c.1065G>C	p.Gln355His	missense	Exon 12 of 29	ENSP00000434830.1	Q7Z2Y5-1
NRK	ENST00000882684.1		c.1065G>C	p.Gln355His	missense	Exon 12 of 28	ENSP00000552743.1
NRK	ENST00000882683.1		c.1065G>C	p.Gln355His	missense	Exon 12 of 28	ENSP00000552742.1

Frequencies

GnomAD3 genomes

AF:

0.000580

AC:

AN:

112120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

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:

0.000661

GnomAD2 exomes

AF:

0.0000877

AC:

AN:

91252

AF XY:

0.0000440

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.0000713

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000331

AC:

AN:

966298

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

276154

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

21586

American (AMR)

AF:

0.0000426

AC:

AN:

23498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17110

East Asian (EAS)

AF:

0.00

AC:

AN:

25975

South Asian (SAS)

AF:

0.00

AC:

AN:

42415

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37237

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

753620

Other (OTH)

AF:

0.0000973

AC:

AN:

41103

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000579

AC:

AN:

112173

Hom.:

Cov.:

AF XY:

0.000437

AC XY:

AN XY:

34337

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

30858

American (AMR)

AF:

0.000284

AC:

AN:

10559

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.00

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53253

Other (OTH)

AF:

0.000652

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000646

ESP6500AA

AF:

0.00170

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000218

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.59

M_CAP

Benign

0.0079

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PhyloP100

0.51

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.1

REVEL

Benign

0.034

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

0.0020

Vest4

0.24

MutPred

0.17

Loss of MoRF binding (P = 0.1156)

MVP

0.21

ClinPred

0.094

GERP RS

0.23

Varity_R

0.36

gMVP

0.28

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over