14-75088602-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033116.6(NEK9):c.2482C>A(p.Pro828Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,613,924 control chromosomes in the GnomAD database, including 48 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (43 hom.)
• Consequence: NEK9 NM_033116.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.08

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032451153).
• BP6: Variant 14-75088602-G-T is Benign according to our data. Variant chr14-75088602-G-T is described in ClinVar as [Benign]. Clinvar id is 726845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00148 (225/152164) while in subpopulation EAS AF= 0.0387 (200/5174). AF 95% confidence interval is 0.0343. There are 5 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK9	NM_033116.6	c.2482C>A	p.Pro828Thr	missense_variant	20/22	ENST00000238616.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK9	ENST00000238616.10	c.2482C>A	p.Pro828Thr	missense_variant	20/22	1	NM_033116.6	P1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152046 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0391

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00318 AC: 799 AN: 251408 Hom.: 16 AF XY: 0.00291 AC XY: 396 AN XY: 135874

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0405

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00133 AC: 1947 AN: 1461760 Hom.: 43 Cov.: 30 AF XY: 0.00132 AC XY: 957 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0421

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152164 Hom.: 5 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74392

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0387

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00215 Hom.: 8

Bravo AF: 0.00188

ExAC AF: 0.00327 AC: 397

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.0093
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.19	B
Vest4		0.49
MVP		0.76
MPC		0.47
ClinPred		0.018	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.20

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: rs36014869; hg19: chr14-75555305; COSMIC: COSV53129921; COSMIC: COSV53129921;