3-27284626-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

NEK10 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 44

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394966.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK10	NM_001394966.1	MANE Select	c.1990G>C	p.Gly664Arg	missense	Exon 22 of 36	NP_001381895.1	A0A8I5KTB8
	NEK10	NM_001394970.1		c.1990G>C	p.Gly664Arg	missense	Exon 22 of 38	NP_001381899.1	Q6ZWH5-1
	NEK10	NM_152534.6		c.1990G>C	p.Gly664Arg	missense	Exon 23 of 39	NP_689747.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK10	ENST00000691995.1	MANE Select	c.1990G>C	p.Gly664Arg	missense	Exon 22 of 36	ENSP00000509472.1	A0A8I5KTB8
	NEK10	ENST00000429845.6	TSL:5	c.1990G>C	p.Gly664Arg	missense	Exon 23 of 39	ENSP00000395849.2	Q6ZWH5-1
	NEK10	ENST00000936071.1		c.1990G>C	p.Gly664Arg	missense	Exon 23 of 38	ENSP00000606130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.93	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.69		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
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs2042441123; hg19: chr3-27326117;