1-211663444-C-G

Position:

chr1-211663444-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002497.4(NEK2):c.1320G>C(p.Gln440His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,612,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q440K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

NEK2
NM_002497.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.743

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK2	NM_002497.4 linkuse as main transcript	c.1320G>C	p.Gln440His	missense_variant	8/8	ENST00000366999.9
NEK2	NM_001204182.2 linkuse as main transcript	c.1111+3662G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK2	ENST00000366999.9 linkuse as main transcript	c.1320G>C	p.Gln440His	missense_variant	8/8	1	NM_002497.4	P1	P51955-1
NEK2	ENST00000540251.5 linkuse as main transcript	c.1111+3662G>C		intron_variant		1
NEK2	ENST00000462283.5 linkuse as main transcript	n.760G>C		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

249140

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000891

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460536

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726420

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.1320G>C (p.Q440H) alteration is located in exon 8 (coding exon 8) of the NEK2 gene. This alteration results from a G to C substitution at nucleotide position 1320, causing the glutamine (Q) at amino acid position 440 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This variant is present in population databases (rs141984487, gnomAD 0.01%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1436576). This variant has not been reported in the literature in individuals affected with NEK2-related conditions. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 440 of the NEK2 protein (p.Gln440His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.51

MutPred

0.25

Gain of sheet (P = 0.0266);

MVP

0.91

MPC

1.1

ClinPred

0.38

GERP RS

4.5

Varity_R

0.17

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over