3-131152512-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024800.5(NEK11):c.772A>G(p.Lys258Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEK11 NM_024800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.551

Genes affected

NEK11 (HGNC:18593): (NIMA related kinase 11) This gene encodes a member of the never in mitosis gene A family of kinases. The encoded protein localizes to the nucleoli, and may function with NEK2A in the S-phase checkpoint. The encoded protein appears to play roles in DNA replication and response to genotoxic stress. Alternatively spliced transcript variants have been described.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09453443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK11	NM_024800.5	c.772A>G	p.Lys258Glu	missense_variant	8/18	ENST00000383366.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK11	ENST00000383366.9	c.772A>G	p.Lys258Glu	missense_variant	8/18	1	NM_024800.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249920 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461270 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.772A>G (p.K258E) alteration is located in exon 8 (coding exon 6) of the NEK11 gene. This alteration results from a A to G substitution at nucleotide position 772, causing the lysine (K) at amino acid position 258 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.19	T;.;.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.095	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.090	N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.27	T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T
Polyphen		0.015	B;B;B;B;B;B
Vest4		0.20
MutPred		0.38		Loss of methylation at K258 (P = 0.0025);Loss of methylation at K258 (P = 0.0025);Loss of methylation at K258 (P = 0.0025);Loss of methylation at K258 (P = 0.0025);Loss of methylation at K258 (P = 0.0025);Loss of methylation at K258 (P = 0.0025);
MVP		0.58
MPC		0.039
ClinPred		0.067	T
GERP RS		0.35
Varity_R		0.10
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs777979775; hg19: chr3-130871356;