rs34324114

chr4-169477323-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001199397.3(NEK1):c.2235T>G(p.Asn745Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,578,452 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (40 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.06

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008582711).
• BP6: Variant 4-169477323-A-C is Benign according to our data. Variant chr4-169477323-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266051.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=1}. Variant chr4-169477323-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3	c.2235T>G	p.Asn745Lys	missense_variant	26/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6	c.2235T>G	p.Asn745Lys	missense_variant	26/36	1	NM_001199397.3	A2

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 618 AN: 151984 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00596

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00465 AC: 919 AN: 197656 Hom.: 3 AF XY: 0.00457 AC XY: 485 AN XY: 106052

Gnomad AFR exome AF: 0.000712

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00262

Gnomad EAS exome AF: 0.0000701

Gnomad SAS exome AF: 0.00218

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00601

Gnomad OTH exome AF: 0.00451

GnomAD4 exome AF: 0.00541 AC: 7714 AN: 1426350 Hom.: 40 Cov.: 31 AF XY: 0.00541 AC XY: 3819 AN XY: 706542

Gnomad4 AFR exome AF: 0.000551

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.00254

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00595

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152102 Hom.: 2 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74394

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.00596

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00425 Hom.: 1

Bravo AF: 0.00296

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00111 AC: 4

ESP6500EA AF: 0.00579 AC: 47

ExAC AF: 0.00379 AC: 453

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2020	This variant is associated with the following publications: (PMID: 28089114, 28935222) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEK1: BS2 -

Short-rib thoracic dysplasia 6 with or without polydactyly Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Motor neuron disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Feb 15, 2024

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
MetaRNN	Benign	0.0086	T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;N;D;N;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.065	T;T;T;T;T
Polyphen		1.0	D;.;D;D;D
Vest4		0.77
MutPred		0.12		Gain of ubiquitination at N717 (P = 0.0162);.;.;.;.;
MVP		0.93
MPC		0.38
ClinPred		0.036	T
GERP RS		5.6
Varity_R		0.71
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34324114; hg19: chr4-170398474;