Genetic Variant NEK8:p.Arg462Gly (chr17-28739168-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_178170.3(NEK8):c.1384C>G(p.Arg462Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R462Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NEK8
NM_178170.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.51

Publications

2 publications found

Variant links:

Genes affected

NEK8 (HGNC:13387): (NIMA related kinase 8) This gene encodes a member of the serine/threionine protein kinase family related to NIMA (never in mitosis, gene A) of Aspergillus nidulans. The encoded protein may play a role in cell cycle progression from G2 to M phase. Mutations in the related mouse gene are associated with a disease phenotype that closely parallels the juvenile autosomal recessive form of polycystic kidney disease in humans. [provided by RefSeq, Jul 2008]

NEK8 Gene-Disease associations (from GenCC):

renal-hepatic-pancreatic dysplasia 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics
autosomal dominant polycystic kidney disease
Inheritance: AD Classification: STRONG Submitted by: ClinGen
nephronophthisis 9
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
polycystic kidney disease 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal-hepatic-pancreatic dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEK8 links:

ENSG00000265073 (HGNC:):

ENSG00000265073 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13125515).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK8	NM_178170.3	MANE Select	c.1384C>G	p.Arg462Gly	missense	Exon 10 of 15	NP_835464.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEK8	ENST00000268766.11	TSL:1 MANE Select	c.1384C>G	p.Arg462Gly	missense	Exon 10 of 15	ENSP00000268766.6
NEK8	ENST00000969681.1		c.1423C>G	p.Arg475Gly	missense	Exon 10 of 15	ENSP00000639740.1
NEK8	ENST00000903448.1		c.1252C>G	p.Arg418Gly	missense	Exon 9 of 14	ENSP00000573507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251488

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.79

M_CAP

Benign

0.023

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.9

PhyloP100

1.5

PrimateAI

Uncertain

0.66

PROVEAN

Benign

1.1

REVEL

Benign

0.13

Sift

Benign

0.44

Sift4G

Benign

0.43

Polyphen

0.0030

Vest4

0.37

MutPred

0.57

Loss of MoRF binding (P = 0.074)

MVP

0.70

MPC

0.36

ClinPred

0.10

GERP RS

2.6

Varity_R

0.074

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over