Genetic Variant NEK1:p.His769Pro (chr4-169477252-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001199397.3(NEK1):c.2306A>C(p.His769Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H769R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NEK1
NM_001199397.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06214243).

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>C	p.His769Pro	missense	Exon 26 of 36	NP_001186326.1	Q96PY6-3
NEK1	NM_001374418.1		c.2306A>C	p.His769Pro	missense	Exon 25 of 35	NP_001361347.1	Q96PY6-3
NEK1	NM_001374419.1		c.2222A>C	p.His741Pro	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>C	p.His769Pro	missense	Exon 26 of 36	ENSP00000424757.2	Q96PY6-3
NEK1	ENST00000439128.6	TSL:1	c.2222A>C	p.His741Pro	missense	Exon 24 of 34	ENSP00000408020.2	Q96PY6-1
NEK1	ENST00000511633.5	TSL:1	c.2174A>C	p.His725Pro	missense	Exon 25 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.1

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.060

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.47

M_CAP

Benign

0.017

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PhyloP100

0.33

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Benign

0.20

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.14

MutPred

0.093

Gain of loop (P = 0.1069)

MVP

0.41

MPC

0.078

ClinPred

0.031

GERP RS

-0.23

Varity_R

0.089

gMVP

0.31

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over