rs55635245

Positions:

• chr1-211675465-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002497.4(NEK2):​c.15T>G​(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,612,816 control chromosomes in the GnomAD database, including 3,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (253 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3173 hom.)
• Consequence: NEK2 NM_002497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.135

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-211675465-A-C is Benign according to our data. Variant chr1-211675465-A-C is described in ClinVar as [Benign]. Clinvar id is 403229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.135 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK2	NM_002497.4	c.15T>G	p.Ala5Ala	synonymous_variant	1/8	ENST00000366999.9	NP_002488.1
NEK2	NM_001204182.2	c.15T>G	p.Ala5Ala	synonymous_variant	1/8		NP_001191111.1
NEK2	NM_001204183.2	c.15T>G	p.Ala5Ala	synonymous_variant	1/7		NP_001191112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK2	ENST00000366999.9	c.15T>G	p.Ala5Ala	synonymous_variant	1/8	1	NM_002497.4	ENSP00000355966.4
NEK2	ENST00000540251.5	c.15T>G	p.Ala5Ala	synonymous_variant	1/8	1		ENSP00000440237.2
NEK2	ENST00000366998.4	c.15T>G	p.Ala5Ala	synonymous_variant	1/7	1		ENSP00000355965.3

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7236 AN: 152234 Hom.: 254 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0573 AC: 14289 AN: 249186 Hom.: 673 AF XY: 0.0549 AC XY: 7405 AN XY: 134868

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0426

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0607

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0616 AC: 90006 AN: 1460464 Hom.: 3173 Cov.: 31 AF XY: 0.0605 AC XY: 43936 AN XY: 726534

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0312

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.0438

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.0666

Gnomad4 OTH exome AF: 0.0543

GnomAD4 genome AF: 0.0475 AC: 7238 AN: 152352 Hom.: 253 Cov.: 33 AF XY: 0.0472 AC XY: 3517 AN XY: 74516

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0412

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0632

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0531 Hom.: 114

Bravo AF: 0.0529

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.0612

EpiControl AF: 0.0582

ClinVar

Significance: 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs55635245; hg19: chr1-211848807;