chr9-124347747-G-A

Position:

• chr9-124347747-G-A

Variant summary

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

The NM_014397.6(NEK6):​c.756G>A​(p.Met252Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEK6 NM_014397.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

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
NEK6	NM_014397.6	c.756G>A	p.Met252Ile	missense_variant	9/10	ENST00000320246.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK6	ENST00000320246.10	c.756G>A	p.Met252Ile	missense_variant	9/10	1	NM_014397.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Sep 23, 2023

The c.858G>A (p.M286I) alteration is located in exon 10 (coding exon 9) of the NEK6 gene. This alteration results from a G to A substitution at nucleotide position 858, causing the methionine (M) at amino acid position 286 to be replaced by an isoleucine (I). 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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Benign	0.97
DEOGEN2	Benign	0.053	.;T;.;T;T;T;T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;.;.;.;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.80	.;N;.;N;N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.062	T;D;D;D;D;T;D;T;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T
Polyphen		0.030	B;B;B;B;B;.;B;B;B
Vest4		0.81
MutPred		0.35		.;Gain of methylation at K251 (P = 0.0267);.;Gain of methylation at K251 (P = 0.0267);Gain of methylation at K251 (P = 0.0267);.;Gain of methylation at K251 (P = 0.0267);.;.;
MVP		0.88
MPC		0.035
ClinPred		0.67	D
GERP RS		4.1
Varity_R		0.41
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-127110026;