3-27284626-C-G

Variant names:

• chr3-27284626-C-G
• rs2042441123
• NM_001394966.1:c.1990G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001394966.1(NEK10):​c.1990G>C​(p.Gly664Arg) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: NEK10 NM_001394966.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

Genes affected

NEK10 (HGNC:18592): (NIMA related kinase 10) Enables protein kinase activity. Involved in several processes, including mucociliary clearance; positive regulation of protein phosphorylation; and regulation of ERK1 and ERK2 cascade. Part of protein kinase complex. Implicated in primary ciliary dyskinesia 44. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK10	NM_001394966.1	c.1990G>C	p.Gly664Arg	missense_variant	Exon 22 of 36	ENST00000691995.1	NP_001381895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK10	ENST00000691995.1	c.1990G>C	p.Gly664Arg	missense_variant	Exon 22 of 36		NM_001394966.1	ENSP00000509472.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1990G>C (p.G664R) alteration is located in exon 23 (coding exon 21) of the NEK10 gene. This alteration results from a G to C substitution at nucleotide position 1990, causing the glycine (G) at amino acid position 664 to be replaced by an arginine (R). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.021	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.93	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.015	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.69		Gain of ubiquitination at K666 (P = 0.0609);Gain of ubiquitination at K666 (P = 0.0609);
MVP		0.61
MPC		0.57
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.78
gMVP		0.62

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: rs2042441123; hg19: chr3-27326117;