Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001199397.3(NEK1):c.2137G>A(p.Val713Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 1,607,920 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V713L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 10 hom. )

Consequence

NEK1
NM_001199397.3 missense, splice_region

Scores

Splicing: ADA: 0.00008406

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.180

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040504336).

BP6

Variant 4-169479405-C-T is Benign according to our data. Variant chr4-169479405-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266049.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000675 (983/1455698) while in subpopulation MID AF = 0.0156 (90/5752). AF 95% confidence interval is 0.013. There are 10 homozygotes in GnomAdExome4. There are 488 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199397.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEK1	NM_001199397.3	MANE Select	c.2137G>A	p.Val713Met	missense splice_region	Exon 24 of 36	NP_001186326.1
NEK1	NM_001374418.1		c.2137G>A	p.Val713Met	missense splice_region	Exon 23 of 35	NP_001361347.1
NEK1	NM_001374419.1		c.2053G>A	p.Val685Met	missense splice_region	Exon 23 of 35	NP_001361348.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEK1	ENST00000507142.6	TSL:1 MANE Select	c.2137G>A	p.Val713Met	missense splice_region	Exon 24 of 36	ENSP00000424757.2
NEK1	ENST00000439128.6	TSL:1	c.2053G>A	p.Val685Met	missense splice_region	Exon 22 of 34	ENSP00000408020.2
NEK1	ENST00000511633.5	TSL:1	c.2005G>A	p.Val669Met	missense splice_region	Exon 23 of 35	ENSP00000423332.1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000618

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000968

AC:

238

AN:

245916

AF XY:

0.000892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000149

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000741

Gnomad OTH exome

AF:

0.00201

GnomAD4 exome

AF:

0.000675

AC:

983

AN:

1455698

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

488

AN XY:

723524

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33282

American (AMR)

AF:

0.000181

AC:

AN:

44162

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

322

AN:

26022

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39556

South Asian (SAS)

AF:

0.000453

AC:

AN:

83900

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000396

AC:

439

AN:

1109538

Other (OTH)

AF:

0.00108

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000650

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.000393

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000618

AC:

AN:

67990

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000891

Hom.:

Bravo

AF:

0.000657

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00111

AC:

ExAC

AF:

0.000836

AC:

101

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Short-rib thoracic dysplasia 6 with or without polydactyly (2)

Motor neuron disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.035

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.079

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.022

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.56

PhyloP100

-0.18

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.35

REVEL

Benign

0.049

Sift

Benign

0.40

Sift4G

Benign

0.24

Polyphen

0.13

Vest4

0.12

MVP

0.50

MPC

0.057

ClinPred

0.017

GERP RS

-5.2

Varity_R

0.023

gMVP

0.035

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000084

dbscSNV1_RF

Benign

0.0040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over