17-28737984-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_178170.3(NEK8):c.1055G>T(p.Arg352Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,611,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

NEK8
NM_178170.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 9.63

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 links:

ENSG00000265073 (HGNC:):

ENSG00000265073 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000334 (487/1459594) while in subpopulation AMR AF= 0.000694 (31/44670). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4_exome. There are 230 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK8	NM_178170.3 link	c.1055G>T	p.Arg352Leu	missense_variant	Exon 7 of 15	ENST00000268766.11	NP_835464.1	Q86SG6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEK8	ENST00000268766.11 link	c.1055G>T	p.Arg352Leu	missense_variant	Exon 7 of 15	1	NM_178170.3	ENSP00000268766.6	Q86SG6
NEK8	ENST00000592510.1 link	c.614G>T	p.Arg205Leu	missense_variant	Exon 4 of 5	3		ENSP00000466476.1	K7EMF0
NEK8	ENST00000543014.1 link	n.1215G>T		non_coding_transcript_exon_variant	Exon 6 of 11	2		ENSP00000465859.1	K7EL04
ENSG00000265073	ENST00000584779.1 link	n.417+4365C>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000303

AC:

AN:

247622

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

134598

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000142

Gnomad NFE exome

AF:

0.000448

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000334

AC:

487

AN:

1459594

Hom.:

Cov.:

AF XY:

0.000317

AC XY:

230

AN XY:

725836

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000694

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000360

Gnomad4 NFE exome

AF:

0.000382

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000458

Hom.:

Bravo

AF:

0.000230

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jan 12, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEK8: PM2:Supporting, PP3 -

Nephronophthisis 9

Uncertain:2

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 352 of the NEK8 protein (p.Arg352Leu). This variant is present in population databases (rs199933041, gnomAD 0.05%). This missense change has been observed in individual(s) with NEK8-related conditions (PMID: 30384889). ClinVar contains an entry for this variant (Variation ID: 198630). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis 9;C3809434:Renal-hepatic-pancreatic dysplasia 2;C5935640:Polycystic kidney disease 8

Uncertain:1

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.84

Sift

Uncertain

0.023

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.93

MVP

0.96

MPC

0.73

ClinPred

0.51

GERP RS

5.6

Varity_R

0.47

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