9-124293011-G-A

Variant names:

• chr9-124293011-G-A
• rs753103515
• ENST00000373600.7:c.71G>A

Variant summary

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

The NM_001145001.3(NEK6):​c.71G>A​(p.Arg24Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000427 in 1,404,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R24L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: NEK6 NM_001145001.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002008
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.277

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08474386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK6	NM_014397.6	c.-29-8925G>A		intron_variant	Intron 1 of 9	ENST00000320246.10	NP_055212.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK6	ENST00000320246.10	c.-29-8925G>A		intron_variant	Intron 1 of 9	1	NM_014397.6	ENSP00000319734.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1404244 Hom.: 0 Cov.: 31 AF XY: 0.00000721 AC XY: 5 AN XY: 693944

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000547

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000680 Hom.: 0

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71G>A (p.R24Q) alteration is located in exon 2 (coding exon 1) of the NEK6 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.5
DANN	Benign	0.78
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.46	.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.11	B;.;B
Vest4		0.099
MutPred		0.34		Loss of methylation at R24 (P = 0.0382);Loss of methylation at R24 (P = 0.0382);Loss of methylation at R24 (P = 0.0382);
MVP		0.42
MPC		0.67
ClinPred		0.60	D
GERP RS		2.9
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs753103515; hg19: chr9-127055290; COSMIC: COSV57220078;