4-169562149-C-T

Position:

• chr4-169562149-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001199397.3(NEK1):​c.1068G>A​(p.Arg356Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.0134 in 1,542,566 control chromosomes in the GnomAD database, including 2,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (1273 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (1021 hom.)
• Consequence: NEK1 NM_001199397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.09

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]

NEK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 4-169562149-C-T is Benign according to our data. Variant chr4-169562149-C-T is described in ClinVar as [Benign]. Clinvar id is 348117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-169562149-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK1	NM_001199397.3	c.1068G>A	p.Arg356Arg	synonymous_variant	13/36	ENST00000507142.6	NP_001186326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6	c.1068G>A	p.Arg356Arg	synonymous_variant	13/36	1	NM_001199397.3	ENSP00000424757.2

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 10840 AN: 151812 Hom.: 1269 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.0556

GnomAD3 exomes AF: 0.0151 AC: 2470 AN: 163598 Hom.: 261 AF XY: 0.0119 AC XY: 1028 AN XY: 86446

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000318

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000922

Gnomad OTH exome AF: 0.00942

GnomAD4 exome AF: 0.00710 AC: 9870 AN: 1390636 Hom.: 1021 Cov.: 27 AF XY: 0.00623 AC XY: 4278 AN XY: 686598

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000544

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000592

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0715 AC: 10858 AN: 151930 Hom.: 1273 Cov.: 32 AF XY: 0.0680 AC XY: 5055 AN XY: 74288

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0305

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00102

Gnomad4 OTH AF: 0.0550

Alfa AF: 0.0324 Hom.: 284

Bravo AF: 0.0819

Asia WGS AF: 0.0140 AC: 49 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Short-rib thoracic dysplasia 6 with or without polydactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs17055010; hg19: chr4-170483300;