rs377607698
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001199397.3(NEK1):c.3140C>T(p.Ser1047Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000558 in 1,613,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1047S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 0 hom. )
Consequence
NEK1
NM_001199397.3 missense
NM_001199397.3 missense
Scores
2
14
3
Clinical Significance
Conservation
PhyloP100: 5.49
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-169424635-G-A is Pathogenic according to our data. Variant chr4-169424635-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266054.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEK1 | NM_001199397.3 | c.3140C>T | p.Ser1047Leu | missense_variant | 31/36 | ENST00000507142.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEK1 | ENST00000507142.6 | c.3140C>T | p.Ser1047Leu | missense_variant | 31/36 | 1 | NM_001199397.3 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248950Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135024
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GnomAD4 exome AF: 0.0000582 AC: 85AN: 1461360Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 39AN XY: 726912
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74320
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Motor neuron disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | case-control | Centre for Genomic and Experimental Medicine, University of Edinburgh | Aug 31, 2016 | - - |
Short-rib thoracic dysplasia 6 with or without polydactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1019 of the NEK1 protein (p.Ser1019Leu). This variant is present in population databases (rs377607698, gnomAD 0.008%). This missense change has been observed in individual(s) with NEK1-related conditions (PMID: 28089114). This variant is also known as c.C3140T; p.S1047L. ClinVar contains an entry for this variant (Variation ID: 266054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NEK1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
T;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;D;D;D
Vest4
MVP
MPC
0.27
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at