17-28741140-C-T

Position:

chr17-28741140-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_178170.3(NEK8):c.1795C>T(p.Arg599Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,988 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NEK8
NM_178170.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 0.811

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-28741140-C-T is Pathogenic according to our data. Variant chr17-28741140-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-28741140-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK8	NM_178170.3 linkuse as main transcript	c.1795C>T	p.Arg599Ter	stop_gained	13/15	ENST00000268766.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NEK8	ENST00000268766.11 linkuse as main transcript	c.1795C>T	p.Arg599Ter	stop_gained	13/15	1	NM_178170.3	P1
	ENST00000584779.1 linkuse as main transcript	n.417+1209G>A		intron_variant, non_coding_transcript_variant		5
NEK8	ENST00000543014.1 linkuse as main transcript	c.*119-359C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251416

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000131

AC:

192

AN:

1461822

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000968

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal-hepatic-pancreatic dysplasia 2

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Mar 23, 2023	This variant was observed in heterozygosity with variant c.618G>A -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2024	Variant summary: NEK8 c.1795C>T (p.Arg599X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.8e-05 in 251416 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEK8 causing Renal-Hepatic Dysplasia 2. c.1795C>T has been reported in the literature in multiple homozygous individuals affected with Renal-Hepatic Dysplasia 2 (e.g., Frank_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function; studies on patient fibroblasts demonstrated a loss of NEK8 expression. The following publication has been ascertained in the context of this evaluation (PMID: 23418306). ClinVar contains an entry for this variant (Variation ID: 65408). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2022	Loss of NEK8 expression was reported in fibroblasts from affected fetuses with this homozygous variant (Frank et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26697755, 30924587, 31980526, 31589614, 23418306, 26862157) -

NEK8-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2024

The NEK8 c.1795C>T variant is predicted to result in premature protein termination (p.Arg599*). This variant has been reported in the homozygous state in three fetuses from one family with renal-hepatic-pancreatic dysplasia (Frank et al. 2013. PubMed ID: 23418306). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in NEK8 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Nephronophthisis 9;C3809434:Renal-hepatic-pancreatic dysplasia 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Premature ovarian insufficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Jan 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.78

MutationTaster

Benign

1.0

Vest4

0.64

GERP RS

2.3

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