9-124321566-C-G

Variant names:

• chr9-124321566-C-G
• NM_014397.6:c.402C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014397.6(NEK6):​c.402C>G​(p.Ile134Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: NEK6 NM_014397.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK6	NM_014397.6	c.402C>G	p.Ile134Met	missense_variant	Exon 5 of 10	ENST00000320246.10	NP_055212.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK6	ENST00000320246.10	c.402C>G	p.Ile134Met	missense_variant	Exon 5 of 10	1	NM_014397.6	ENSP00000319734.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.504C>G (p.I168M) alteration is located in exon 6 (coding exon 5) of the NEK6 gene. This alteration results from a C to G substitution at nucleotide position 504, causing the isoleucine (I) at amino acid position 168 to be replaced by a methionine (M). 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	0.29
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T;.;T;T;T;T;T;.;.;T;T;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;.;.;.;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.1	.;M;.;M;M;.;.;.;.;.;M;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.;.;.;.;D;.;D;D;.
Vest4		0.83
MutPred		0.68		.;Gain of disorder (P = 0.0649);.;Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);.;Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);.;Gain of disorder (P = 0.0649);Gain of disorder (P = 0.0649);.;.;Gain of disorder (P = 0.0649);
MVP		0.86
MPC		2.2
ClinPred		0.94	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.70

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: chr9-127083845;