rs758677637
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The ENST00000507142.6(NEK1):c.1618C>T(p.Arg540Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000754 in 1,459,168 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 (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
NEK1
ENST00000507142.6 stop_gained
ENST00000507142.6 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.79
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 11 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 4-169537856-G-A is Pathogenic according to our data. Variant chr4-169537856-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446667.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEK1 | NM_001199397.3 | c.1618C>T | p.Arg540Ter | stop_gained | 19/36 | ENST00000507142.6 | NP_001186326.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEK1 | ENST00000507142.6 | c.1618C>T | p.Arg540Ter | stop_gained | 19/36 | 1 | NM_001199397.3 | ENSP00000424757 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247770Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134466
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GnomAD4 exome AF: 0.00000754 AC: 11AN: 1459168Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4AN XY: 725860
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:2
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
NEK1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 11, 2024 | The NEK1 c.1618C>T variant is predicted to result in premature protein termination (p.Arg540*). This variant was reported along with a second premature termination variant in a patient with short-rib thoracic dysplasia type II (Table S2, Zhang et al. 2017. PubMed ID: 29068549). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD, including 11 heterozygous individuals in the gnomAD v4.1.0 dataset (https://gnomad.broadinstitute.org/variant/4-169537856-G-A?dataset=gnomad_r4). Nonsense variants in NEK1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
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