17-28741140-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.Arg599*) 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

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U: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]

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 rank MANE Protein UniProt
NEK8NM_178170.3 linkc.1795C>T p.Arg599* stop_gained Exon 13 of 15 ENST00000268766.11 NP_835464.1 Q86SG6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEK8ENST00000268766.11 linkc.1795C>T p.Arg599* stop_gained Exon 13 of 15 1 NM_178170.3 ENSP00000268766.6 Q86SG6
NEK8ENST00000543014.1 linkn.*119-359C>T intron_variant Intron 9 of 10 2 ENSP00000465859.1 K7EL04
ENSG00000265073ENST00000584779.1 linkn.417+1209G>A intron_variant Intron 1 of 1 5

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152166
Hom.:
0
Cov.:
32
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:
17
AN:
251416
Hom.:
0
AF XY:
0.0000515
AC XY:
7
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.:
0
Cov.:
35
AF XY:
0.000132
AC XY:
96
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:
11
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
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.:
0
Bravo
AF:
0.0000680
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Renal-hepatic-pancreatic dysplasia 2 Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 02, 2024Variant 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2013- -
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research CentreMar 29, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneMar 23, 2023This variant was observed in heterozygosity with variant c.618G>A -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 19, 2022Loss 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) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
NEK8-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 01, 2024The 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 06, 2022- -
Nephronophthisis 9 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 13, 2024This sequence change creates a premature translational stop signal (p.Arg599*) in the NEK8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEK8 are known to be pathogenic (PMID: 23418306, 26967905). This variant is present in population databases (rs375661404, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive NEK8-related conditions (PMID: 23418306). ClinVar contains an entry for this variant (Variation ID: 65408). For these reasons, this variant has been classified as Pathogenic. -
Premature ovarian insufficiency Uncertain:1
Uncertain significance, no assertion criteria providedresearchReproductive Development, Murdoch Childrens Research InstituteJan 10, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.78
D
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.

Other links and lift over

dbSNP: rs375661404; hg19: chr17-27068158; COSMIC: COSV52044406; COSMIC: COSV52044406; API