rs35222922

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001199397.3(NEK1):c.859C>G(p.Pro287Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,529,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.22

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis, susceptibility to, 24
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
short-rib thoracic dysplasia 6 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome type II
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Majewski type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005516529).

BP6

Variant 4-169580851-G-C is Benign according to our data. Variant chr4-169580851-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 598999.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000158 (24/151844) while in subpopulation EAS AF = 0.00426 (22/5166). AF 95% confidence interval is 0.00288. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK1	NM_001199397.3 link	c.859C>G	p.Pro287Ala	missense_variant	Exon 11 of 36	ENST00000507142.6	NP_001186326.1	Q96PY6-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6 link	c.859C>G	p.Pro287Ala	missense_variant	Exon 11 of 36	1	NM_001199397.3	ENSP00000424757.2		Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00425

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000388

AC:

AN:

152054

AF XY:

0.000435

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

148

AN:

1377240

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

680154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30930

American (AMR)

AF:

0.00

AC:

AN:

34752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24964

East Asian (EAS)

AF:

0.00329

AC:

116

AN:

35216

South Asian (SAS)

AF:

0.000181

AC:

AN:

77256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

9.42e-7

AC:

AN:

1061954

Other (OTH)

AF:

0.000297

AC:

AN:

57296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000158

AC:

AN:

151844

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41488

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00426

AC:

AN:

5166

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67952

Other (OTH)

AF:

0.000475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000238

ExAC

AF:

0.000101

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NEK1 c.859C>G; p.Pro287Ala variant (rs35222922) is reported in the literature in individuals affected with amyotrophic lateral sclerosis (Pang 2017), but has not been reported in association with skeletal dysplasia. This variant is reported in ClinVar (Variation ID: 598999), and is found in the East Asian population with an allele frequency of 0.59% (72/12112 alleles) in the Genome Aggregation Database. The proline at codon 287 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro287Ala variant is uncertain at this time. References: Pang et al. Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. Neurobiol Aging. 2017 Oct;58:238.e9-238.e15. -

Connective tissue disorder

Uncertain:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEK1-related disorder

Benign:1

May 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Short-rib thoracic dysplasia 6 with or without polydactyly

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.18

DEOGEN2

Benign

0.062

T;.;.;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0055

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

L;L;L;L;L

PhyloP100

2.2

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.064

Sift

Benign

0.42

T;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.0020

B;.;B;B;B

Vest4

0.11

MVP

0.70

MPC

0.053

ClinPred

0.026

GERP RS

4.8

Varity_R

0.083

gMVP

0.27

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over