rs6828134

chr4-169438116-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199397.3(NEK1):c.2731C>G(p.Gln911Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,612,356 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032262504).
• BP6: Variant 4-169438116-G-C is Benign according to our data. Variant chr4-169438116-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 527126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-169438116-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00489 (745/152324) while in subpopulation AFR AF= 0.0173 (721/41566). AF 95% confidence interval is 0.0163. There are 5 homozygotes in gnomad4. There are 338 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3	c.2731C>G	p.Gln911Glu	missense_variant	28/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6	c.2731C>G	p.Gln911Glu	missense_variant	28/36	1	NM_001199397.3	A2

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 745 AN: 152206 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00119 AC: 293 AN: 246646 Hom.: 2 AF XY: 0.000906 AC XY: 121 AN XY: 133626

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000511 AC: 746 AN: 1460032 Hom.: 6 Cov.: 30 AF XY: 0.000461 AC XY: 335 AN XY: 726048

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.000539

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000933

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152324 Hom.: 5 Cov.: 33 AF XY: 0.00454 AC XY: 338 AN XY: 74486

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000699 Hom.: 2

Bravo AF: 0.00570

ESP6500AA AF: 0.0161 AC: 59

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00151 AC: 182

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2023	See Variant Classification Assertion Criteria. -

Short-rib thoracic dysplasia 6 with or without polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	14
Dann	Benign	0.62
DEOGEN2	Benign	0.050	T;.;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
MetaRNN	Benign	0.0032	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M;.;.;.;.
MutationTaster	Benign	0.52	D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.0010	B;.;B;B;B
Vest4		0.089
MVP		0.67
MPC		0.058
ClinPred		0.017	T
GERP RS		4.2
Varity_R		0.080
gMVP		0.057

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: rs6828134; hg19: chr4-170359267; COSMIC: COSV99073142;