14-75091355-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_033116.6(NEK9):c.2357G>A(p.Arg786Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,614,118 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: NEK9 NM_033116.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

Genes affected

NEK9 (HGNC:18591): (NIMA related kinase 9) This gene encodes a member of the NimA (never in mitosis A) family of serine/threonine protein kinases. The encoded protein is activated in mitosis and, in turn, activates other family members during mitosis. This protein also mediates cellular processes that are essential for interphase progression. [provided by RefSeq, Jul 2016]

ZC2HC1C (HGNC:20354): (zinc finger C2HC-type containing 1C) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072137117).
• BP6: Variant 14-75091355-C-T is Benign according to our data. Variant chr14-75091355-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 717455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0031 (472/152342) while in subpopulation AFR AF= 0.0106 (441/41572). AF 95% confidence interval is 0.00979. There are 1 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK9	NM_033116.6	c.2357G>A	p.Arg786Gln	missense_variant	19/22	ENST00000238616.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK9	ENST00000238616.10	c.2357G>A	p.Arg786Gln	missense_variant	19/22	1	NM_033116.6	P1

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 471 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000999 AC: 251 AN: 251278 Hom.: 1 AF XY: 0.000773 AC XY: 105 AN XY: 135814

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000503 AC: 736 AN: 1461776 Hom.: 1 Cov.: 30 AF XY: 0.000477 AC XY: 347 AN XY: 727186

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74502

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000900 Hom.: 1

Bravo AF: 0.00368

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00112 AC: 136

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEK9: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.73	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.14
Sift	Benign	0.039	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.21
MVP		0.79
MPC		0.45
ClinPred		0.014	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.42

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

Other links and lift over

dbSNP: rs114347531; hg19: chr14-75558058; COSMIC: COSV53130216;