4-169477252-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001199397.3(NEK1):c.2306A>G(p.His769Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,600,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.333

Publications

1 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0635865).

BP6

Variant 4-169477252-T-C is Benign according to our data. Variant chr4-169477252-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266050.

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	UniProt
NEK1	NM_001199397.3	MANE Select	c.2306A>G	p.His769Arg	missense	Exon 26 of 36	NP_001186326.1	Q96PY6-3
NEK1	NM_001374418.1		c.2306A>G	p.His769Arg	missense	Exon 25 of 35	NP_001361347.1	Q96PY6-3
NEK1	NM_001374419.1		c.2222A>G	p.His741Arg	missense	Exon 25 of 35	NP_001361348.1	Q96PY6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEK1	ENST00000507142.6	TSL:1 MANE Select	c.2306A>G	p.His769Arg	missense	Exon 26 of 36	ENSP00000424757.2	Q96PY6-3
NEK1	ENST00000439128.6	TSL:1	c.2222A>G	p.His741Arg	missense	Exon 24 of 34	ENSP00000408020.2	Q96PY6-1
NEK1	ENST00000511633.5	TSL:1	c.2174A>G	p.His725Arg	missense	Exon 25 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152074

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000308

AC:

AN:

227478

AF XY:

0.0000326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000698

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000352

AC:

AN:

1448322

Hom.:

Cov.:

AF XY:

0.0000389

AC XY:

AN XY:

719114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33276

American (AMR)

AF:

0.00

AC:

AN:

43122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25848

East Asian (EAS)

AF:

0.00

AC:

AN:

39400

South Asian (SAS)

AF:

0.0000238

AC:

AN:

84144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52748

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000408

AC:

AN:

1104188

Other (OTH)

AF:

0.0000167

AC:

AN:

59844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.0000197

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67918

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Motor neuron disease (1)

NEK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.60

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.057

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.75

M_CAP

Benign

0.035

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

0.33

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

REVEL

Benign

0.10

Sift

Benign

0.29

Sift4G

Benign

0.40

Polyphen

0.0050

Vest4

0.15

MVP

0.50

MPC

0.066

ClinPred

0.040

GERP RS

-0.23

Varity_R

0.046

gMVP

0.26

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over