NM_178170.3:c.1055G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_178170.3(NEK8):c.1055G>A(p.Arg352His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R352L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NEK8
NM_178170.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.63

Publications

4 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

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.1055G>A	p.Arg352His	missense	Exon 7 of 15	NP_835464.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEK8	ENST00000268766.11	TSL:1 MANE Select	c.1055G>A	p.Arg352His	missense	Exon 7 of 15	ENSP00000268766.6
NEK8	ENST00000592510.1	TSL:3	c.614G>A	p.Arg205His	missense	Exon 4 of 5	ENSP00000466476.1
NEK8	ENST00000543014.1	TSL:2	n.1215G>A		non_coding_transcript_exon	Exon 6 of 11	ENSP00000465859.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247622

AF XY:

0.00000743

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:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459594

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110812

Other (OTH)

AF:

0.0000332

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.1

PhyloP100

9.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.80

Sift

Uncertain

0.019

Sift4G

Uncertain

0.054

Polyphen

1.0

Vest4

0.91

MutPred

0.60

Loss of MoRF binding (P = 0.0118)

MVP

0.96

MPC

1.0

ClinPred

0.94

GERP RS

5.6

Varity_R

0.24

Mutation Taster

=69/31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over