Genetic Variant NEK6:p.Gln4Arg (chr9-124301975-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014397.6(NEK6):c.11A>G(p.Gln4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000375 in 1,599,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

NEK6
NM_014397.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.35

Variant links:

Genes affected

NEK6 (HGNC:7749): (NIMA related kinase 6) The protein encoded by this gene is a kinase required for progression through the metaphase portion of mitosis. Inhibition of the encoded protein can lead to apoptosis. This protein also can enhance tumorigenesis by suppressing tumor cell senescence. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

NEK6 links:

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ACMG classification

Classification made for transcript

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=0.22284934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK6	NM_014397.6 link	c.11A>G	p.Gln4Arg	missense_variant	Exon 2 of 10	ENST00000320246.10	NP_055212.2	Q9HC98-1A0A024R8A6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK6	ENST00000320246.10 link	c.11A>G	p.Gln4Arg	missense_variant	Exon 2 of 10	1	NM_014397.6	ENSP00000319734.5		Q9HC98-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000309

AC:

AN:

226432

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122424

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000353

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1447650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718854

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113A>G (p.Q38R) alteration is located in exon 3 (coding exon 2) of the NEK6 gene. This alteration results from a A to G substitution at nucleotide position 113, causing the glutamine (Q) at amino acid position 38 to be replaced by an arginine (R). 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

0.099

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0062

.;T;.;T;T;T;T;T;.;.;T;T;.;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.82

T;.;.;.;.;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.22

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.024

MutationAssessor

Benign

0.81

.;L;.;L;L;.;.;.;.;.;L;.;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.60

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;T;D;D;D;D;D;D;T;D;D;D;T;D

Sift4G

Benign

0.33

T;T;T;T;T;T;D;T;T;D;T;T;T;T;T

Polyphen

0.91

P;P;P;P;P;.;.;.;.;.;P;.;P;P;.

Vest4

0.63

MutPred

0.29

.;Gain of methylation at Q4 (P = 0.0075);.;Gain of methylation at Q4 (P = 0.0075);Gain of methylation at Q4 (P = 0.0075);Gain of methylation at Q4 (P = 0.0075);Gain of methylation at Q4 (P = 0.0075);Gain of methylation at Q4 (P = 0.0075);Gain of methylation at Q4 (P = 0.0075);.;Gain of methylation at Q4 (P = 0.0075);Gain of methylation at Q4 (P = 0.0075);.;.;Gain of methylation at Q4 (P = 0.0075);

MVP

0.75

MPC

0.40

ClinPred

0.29

GERP RS

4.8

Varity_R

0.38

gMVP

0.55

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