rs34324114

Positions:

chr4-169477323-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001199397.3(NEK1):c.2235T>G(p.Asn745Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,578,452 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 40 hom. )

Consequence

NEK1
NM_001199397.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.06

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008582711).

BP6

Variant 4-169477323-A-C is Benign according to our data. Variant chr4-169477323-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266051.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}. Variant chr4-169477323-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK1	NM_001199397.3 linkuse as main transcript	c.2235T>G	p.Asn745Lys	missense_variant	26/36	ENST00000507142.6	NP_001186326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6 linkuse as main transcript	c.2235T>G	p.Asn745Lys	missense_variant	26/36	1	NM_001199397.3	ENSP00000424757	A2	Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.00407

AC:

618

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00596

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00465

AC:

919

AN:

197656

Hom.:

AF XY:

0.00457

AC XY:

485

AN XY:

106052

show subpopulations

Gnomad AFR exome

AF:

0.000712

Gnomad AMR exome

AF:

0.000488

Gnomad ASJ exome

AF:

0.00262

Gnomad EAS exome

AF:

0.0000701

Gnomad SAS exome

AF:

0.00218

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.00601

Gnomad OTH exome

AF:

0.00451

GnomAD4 exome

AF:

0.00541

AC:

7714

AN:

1426350

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

3819

AN XY:

706542

show subpopulations

Gnomad4 AFR exome

AF:

0.000551

Gnomad4 AMR exome

AF:

0.000428

Gnomad4 ASJ exome

AF:

0.00254

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.00193

Gnomad4 FIN exome

AF:

0.0147

Gnomad4 NFE exome

AF:

0.00595

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.00406

AC:

618

AN:

152102

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000721

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0144

Gnomad4 NFE

AF:

0.00596

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00425

Hom.:

Bravo

AF:

0.00296

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00111

AC:

ESP6500EA

AF:

0.00579

AC:

ExAC

AF:

0.00379

AC:

453

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NEK1: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2020	This variant is associated with the following publications: (PMID: 28089114, 28935222) -

Short-rib thoracic dysplasia 6 with or without polydactyly

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Motor neuron disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Feb 15, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D;D

MetaRNN

Benign

0.0086

T;T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.8

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.7

D;N;D;N;D

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Benign

0.065

T;T;T;T;T

Polyphen

1.0

D;.;D;D;D

Vest4

0.77

MutPred

0.12

Gain of ubiquitination at N717 (P = 0.0162);.;.;.;.;

MVP

0.93

MPC

0.38

ClinPred

0.036

GERP RS

5.6

Varity_R

0.71

gMVP

0.52

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