rs371575563
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001199397.3(NEK1):c.1648C>T(p.Arg550Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,612,298 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
NEK1
NM_001199397.3 stop_gained
NM_001199397.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.01
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 12 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 4-169537826-G-A is Pathogenic according to our data. Variant chr4-169537826-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 495120.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEK1 | NM_001199397.3 | c.1648C>T | p.Arg550Ter | stop_gained | 19/36 | ENST00000507142.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEK1 | ENST00000507142.6 | c.1648C>T | p.Arg550Ter | stop_gained | 19/36 | 1 | NM_001199397.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152050Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248560Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134872
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460248Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726462
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74252
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 27, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NEK1 are known to be pathogenic (PMID: 22499340, 29068549). This variant has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 27455347). ClinVar contains an entry for this variant (Variation ID: 495120). This variant is present in population databases (rs371575563, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Arg550*) in the NEK1 gene. It is expected to result in an absent or disrupted protein product. - |
Amyotrophic lateral sclerosis, susceptibility to, 24 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Feb 28, 2018 | - - |
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