rs2289725

Variant names:

• chr1-211670267-C-A
• rs2289725
• NM_002497.4:c.765+14G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002497.4(NEK2):​c.765+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,604,186 control chromosomes in the GnomAD database, including 2,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (229 hom., cov: 33)
  • Exomes 𝑓: 0.042 (2075 hom.)
• Consequence: NEK2 NM_002497.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.287
• Publications: 2 publications found

Genes affected

NEK2 (HGNC:7745): (NIMA related kinase 2) This gene encodes a serine/threonine-protein kinase that is involved in mitotic regulation. This protein is localized to the centrosome, and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase. Alternatively spliced transcript variants encoding different isoforms with distinct C-termini have been noted for this gene. [provided by RefSeq, Feb 2011]

NEK2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 67

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-211670267-C-A is Benign according to our data. Variant chr1-211670267-C-A is described in ClinVar as [Benign]. Clinvar id is 403227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK2	NM_002497.4	c.765+14G>T		intron_variant	Intron 5 of 7	ENST00000366999.9	NP_002488.1
NEK2	NM_001204182.2	c.765+14G>T		intron_variant	Intron 5 of 7		NP_001191111.1
NEK2	NM_001204183.2	c.765+14G>T		intron_variant	Intron 5 of 6		NP_001191112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK2	ENST00000366999.9	c.765+14G>T		intron_variant	Intron 5 of 7	1	NM_002497.4	ENSP00000355966.4
NEK2	ENST00000540251.5	c.765+14G>T		intron_variant	Intron 5 of 7	1		ENSP00000440237.2
NEK2	ENST00000366998.4	c.765+14G>T		intron_variant	Intron 5 of 6	1		ENSP00000355965.3
NEK2	ENST00000462283.5	n.229+14G>T		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5775 AN: 152176 Hom.: 227 Cov.: 33

Gnomad AFR AF: 0.00796

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.0743

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0579 AC: 14364 AN: 248146 AF XY: 0.0586

Gnomad AFR exome AF: 0.00698

Gnomad AMR exome AF: 0.0461

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0559

GnomAD4 exome AF: 0.0423 AC: 61450 AN: 1451892 Hom.: 2075 Cov.: 29 AF XY: 0.0435 AC XY: 31452 AN XY: 722340

African (AFR) AF: 0.00777 AC: 258 AN: 33200

American (AMR) AF: 0.0463 AC: 2042 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 1971 AN: 25992

East Asian (EAS) AF: 0.199 AC: 7882 AN: 39586

South Asian (SAS) AF: 0.0634 AC: 5395 AN: 85038

European-Finnish (FIN) AF: 0.0381 AC: 2034 AN: 53370

Middle Eastern (MID) AF: 0.0765 AC: 336 AN: 4390

European-Non Finnish (NFE) AF: 0.0346 AC: 38284 AN: 1106222

Other (OTH) AF: 0.0542 AC: 3248 AN: 59958

GnomAD4 genome AF: 0.0379 AC: 5777 AN: 152294 Hom.: 229 Cov.: 33 AF XY: 0.0402 AC XY: 2990 AN XY: 74456

African (AFR) AF: 0.00796 AC: 331 AN: 41572

American (AMR) AF: 0.0440 AC: 674 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0743 AC: 258 AN: 3472

East Asian (EAS) AF: 0.226 AC: 1170 AN: 5176

South Asian (SAS) AF: 0.0653 AC: 315 AN: 4826

European-Finnish (FIN) AF: 0.0372 AC: 395 AN: 10608

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0369 AC: 2512 AN: 68018

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0401 Hom.: 80

Bravo AF: 0.0378

Asia WGS AF: 0.152 AC: 527 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.6
DANN	Benign	0.66
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289725; hg19: chr1-211843609; COSMIC: COSV65355209; COSMIC: COSV65355209;