1-211663496-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002497.4(NEK2):c.1268G>A(p.Arg423Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,800 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. R423W) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
NEK2
NM_002497.4 missense
NM_002497.4 missense
Scores
4
4
11
Clinical Significance
Conservation
PhyloP100: 4.88
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]
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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 | c.1268G>A | p.Arg423Gln | missense_variant | 8/8 | ENST00000366999.9 | |
NEK2 | NM_001204182.2 | c.1111+3610G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEK2 | ENST00000366999.9 | c.1268G>A | p.Arg423Gln | missense_variant | 8/8 | 1 | NM_002497.4 | P1 | |
NEK2 | ENST00000540251.5 | c.1111+3610G>A | intron_variant | 1 | |||||
NEK2 | ENST00000462283.5 | n.708G>A | non_coding_transcript_exon_variant | 5/5 | 2 | ||||
NEK2 | ENST00000489633.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250700Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135548
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461616Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727108
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1378965). This variant has not been reported in the literature in individuals affected with NEK2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 423 of the NEK2 protein (p.Arg423Gln). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of helix (P = 0.0117);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at