chr17-28741140-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_178170.3(NEK8):c.1795C>T(p.Arg599*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,988 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_178170.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEK8 | ENST00000268766.11 | c.1795C>T | p.Arg599* | stop_gained | Exon 13 of 15 | 1 | NM_178170.3 | ENSP00000268766.6 | ||
NEK8 | ENST00000543014.1 | n.*119-359C>T | intron_variant | Intron 9 of 10 | 2 | ENSP00000465859.1 | ||||
ENSG00000265073 | ENST00000584779.1 | n.417+1209G>A | intron_variant | Intron 1 of 1 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251416Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135896
GnomAD4 exome AF: 0.000131 AC: 192AN: 1461822Hom.: 0 Cov.: 35 AF XY: 0.000132 AC XY: 96AN XY: 727224
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74332
ClinVar
Submissions by phenotype
Renal-hepatic-pancreatic dysplasia 2 Pathogenic:4
Variant summary: NEK8 c.1795C>T (p.Arg599X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.8e-05 in 251416 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEK8 causing Renal-Hepatic Dysplasia 2. c.1795C>T has been reported in the literature in multiple homozygous individuals affected with Renal-Hepatic Dysplasia 2 (e.g., Frank_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function; studies on patient fibroblasts demonstrated a loss of NEK8 expression. The following publication has been ascertained in the context of this evaluation (PMID: 23418306). ClinVar contains an entry for this variant (Variation ID: 65408). Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
- -
This variant was observed in heterozygosity with variant c.618G>A -
not provided Pathogenic:4
Loss of NEK8 expression was reported in fibroblasts from affected fetuses with this homozygous variant (Frank et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26697755, 30924587, 31980526, 31589614, 23418306, 26862157) -
- -
- -
- -
NEK8-related disorder Pathogenic:1
The NEK8 c.1795C>T variant is predicted to result in premature protein termination (p.Arg599*). This variant has been reported in the homozygous state in three fetuses from one family with renal-hepatic-pancreatic dysplasia (Frank et al. 2013. PubMed ID: 23418306). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in NEK8 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Nephronophthisis 9;C3809434:Renal-hepatic-pancreatic dysplasia 2 Pathogenic:1
- -
Nephronophthisis 9 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg599*) in the NEK8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEK8 are known to be pathogenic (PMID: 23418306, 26967905). This variant is present in population databases (rs375661404, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive NEK8-related conditions (PMID: 23418306). ClinVar contains an entry for this variant (Variation ID: 65408). For these reasons, this variant has been classified as Pathogenic. -
Premature ovarian insufficiency Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at