rs1555564134

chr17-28737428-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_178170.3(NEK8):c.743del(p.Pro248HisfsTer56) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P248P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEK8 NM_178170.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.88

Genes affected

NEK8 (HGNC:13387): (NIMA related kinase 8) This gene encodes a member of the serine/threionine protein kinase family related to NIMA (never in mitosis, gene A) of Aspergillus nidulans. The encoded protein may play a role in cell cycle progression from G2 to M phase. Mutations in the related mouse gene are associated with a disease phenotype that closely parallels the juvenile autosomal recessive form of polycystic kidney disease in humans. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

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 17-28737428-AC-A is Pathogenic according to our data. Variant chr17-28737428-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 471779.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK8	NM_178170.3	c.743del	p.Pro248HisfsTer56	frameshift_variant	5/15	ENST00000268766.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK8	ENST00000268766.11	c.743del	p.Pro248HisfsTer56	frameshift_variant	5/15	1	NM_178170.3	P1
	ENST00000584779.1	n.418-4442del		intron_variant, non_coding_transcript_variant		5
NEK8	ENST00000592510.1	c.219del	p.Pro74HisfsTer84	frameshift_variant	2/5	3
NEK8	ENST00000543014.1	c.743del	p.Pro248HisfsTer52	frameshift_variant, NMD_transcript_variant	5/11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 06, 2017

This sequence change deletes 1 nucleotide from exon 5 of the NEK8 mRNA (c.743delC), causing a frameshift at codon 248. This creates a premature translational stop signal (p.Pro248Hisfs*56) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in NEK8 are known to be pathogenic (PMID: 23418306). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555564134; hg19: chr17-27064446;