chr14-75106541-G-C

Variant names:

• chr14-75106541-G-C
• rs757011098
• NM_033116.6:c.1489C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001329237.2(NEK9):​c.1489C>G​(p.Arg497Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NEK9 NM_001329237.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24
• Publications: 6 publications found

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]

ZC2HC1C Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329237.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK9	NM_033116.6	MANE Select	c.1489C>G	p.Arg497Gly	missense	Exon 12 of 22	NP_149107.4
	NEK9	NM_001329237.2		c.1489C>G	p.Arg497Gly	missense	Exon 12 of 22	NP_001316166.1
	NEK9	NM_001329238.2		c.1135C>G	p.Arg379Gly	missense	Exon 12 of 22	NP_001316167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK9	ENST00000238616.10	TSL:1 MANE Select	c.1489C>G	p.Arg497Gly	missense	Exon 12 of 22	ENSP00000238616.5
	NEK9	ENST00000678037.1		c.1489C>G	p.Arg497Gly	missense	Exon 12 of 22	ENSP00000504620.1
	NEK9	ENST00000909801.1		c.1489C>G	p.Arg497Gly	missense	Exon 12 of 22	ENSP00000579860.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.70	N
PhyloP100		6.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.38
Sift	Benign	0.15	T
Sift4G	Uncertain	0.050	T
Polyphen		0.76	P
Vest4		0.56
MutPred		0.43		Loss of stability (P = 0.0616)
MVP		0.83
MPC		0.86
ClinPred		0.75	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.46
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757011098; hg19: chr14-75573244;