rs202115635

Variant summary

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

The NM_001199397.3(NEK1):c.481C>T(p.Arg161Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000517 in 1,547,228 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,other (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic; other criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 4.78

Variant links:

Genes affected

NEK1 (HGNC:7744): (NIMA related kinase 1) The protein encoded by this gene is a serine/threonine kinase involved in cell cycle regulation. The encoded protein is found in a centrosomal complex with FEZ1, a neuronal protein that plays a role in axonal development. Defects in this gene are a cause of polycystic kidney disease (PKD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

NEK1 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 4-169588719-G-A is Pathogenic according to our data. Variant chr4-169588719-G-A is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 266058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3 linkuse as main transcript	c.481C>T	p.Arg161Ter	stop_gained	8/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6 linkuse as main transcript	c.481C>T	p.Arg161Ter	stop_gained	8/36	1	NM_001199397.3	A2	Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000114

AC:

AN:

158166

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

83376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.00164

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000324

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1395086

Hom.:

Cov.:

AF XY:

0.0000683

AC XY:

AN XY:

688444

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00183

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000140

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000875

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000615

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic; other

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

NEK1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The NEK1 c.481C>T variant is predicted to result in premature protein termination (p.Arg161*). This variant has been reported in one individual with amyotrophic lateral sclerosis (ALS, Table S4, Black et al. 2016. PubMed ID: 28089114). Protein-truncating variants upstream and downstream of this variant have been reported to be pathogenic (HGMD, ClinVar). However, the c.481C>T variant has been reported in 20 and 80 heterozygous individuals in gnomAD v2 and v4, respectively. Protein-truncating variants in NEK1 are expected to be pathogenic; however, they do display incomplete penetrance. At this time, we interpret this variant as likely pathogenic with incomplete penetrance. -

Short-rib thoracic dysplasia 6 with or without polydactyly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2022

This sequence change creates a premature translational stop signal (p.Arg161*) in the NEK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEK1 are known to be pathogenic (PMID: 22499340, 29068549). This variant is present in population databases (rs202115635, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with NEK1-related conditions (PMID: 28089114, 29431110). ClinVar contains an entry for this variant (Variation ID: 266058). For these reasons, this variant has been classified as Pathogenic. -

Motor neuron disease

Other:1

other, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

Loss-of-function but lacking segregation data Loss-of-function

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.90

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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