rs202115635
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001199397.3(NEK1):c.481C>T(p.Arg161Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000517 in 1,547,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,other (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )
Consequence
NEK1
NM_001199397.3 stop_gained
NM_001199397.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.78
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-169588719-G-A is Pathogenic according to our data. Variant chr4-169588719-G-A is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 266058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEK1 | NM_001199397.3 | c.481C>T | p.Arg161Ter | stop_gained | 8/36 | ENST00000507142.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEK1 | ENST00000507142.6 | c.481C>T | p.Arg161Ter | stop_gained | 8/36 | 1 | NM_001199397.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000658 AC: 10AN: 152024Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000114 AC: 18AN: 158166Hom.: 0 AF XY: 0.000132 AC XY: 11AN XY: 83376
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GnomAD4 exome AF: 0.0000502 AC: 70AN: 1395086Hom.: 0 Cov.: 27 AF XY: 0.0000683 AC XY: 47AN XY: 688444
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74370
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ClinVar
Significance: Pathogenic/Likely pathogenic; other
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
NEK1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2024 | The NEK1 c.481C>T variant is predicted to result in premature protein termination (p.Arg161*). This variant has been reported in one individual with amyotrophic lateral sclerosis (ALS, Table S4, Black et al. 2016. PubMed ID: 28089114). Protein-truncating variants upstream and downstream of this variant have been reported to be pathogenic (HGMD, ClinVar). However, the c.481C>T variant has been reported in 20 and 80 heterozygous individuals in gnomAD v2 and v4, respectively. Protein-truncating variants in NEK1 are expected to be pathogenic; however, they do display incomplete penetrance. At this time, we interpret this variant as likely pathogenic with incomplete penetrance. - |
Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 30, 2022 | This sequence change creates a premature translational stop signal (p.Arg161*) in the NEK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEK1 are known to be pathogenic (PMID: 22499340, 29068549). This variant is present in population databases (rs202115635, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with NEK1-related conditions (PMID: 28089114, 29431110). ClinVar contains an entry for this variant (Variation ID: 266058). For these reasons, this variant has been classified as Pathogenic. - |
Motor neuron disease Other:1
other, criteria provided, single submitter | case-control | Centre for Genomic and Experimental Medicine, University of Edinburgh | Aug 31, 2016 | Loss-of-function but lacking segregation data Loss-of-function |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
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