1-211663444-C-A

Variant names:

• chr1-211663444-C-A
• rs141984487
• NM_002497.4:c.1320G>T

Variant summary

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

The NM_002497.4(NEK2):​c.1320G>T​(p.Gln440His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q440K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEK2 NM_002497.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.743
• Publications: 1 publications found

Genes affected

NEK2 (HGNC:7745): (NIMA related kinase 2) This gene encodes a serine/threonine-protein kinase that is involved in mitotic regulation. This protein is localized to the centrosome, and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase. Alternatively spliced transcript variants encoding different isoforms with distinct C-termini have been noted for this gene. [provided by RefSeq, Feb 2011]

NEK2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 67

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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_002497.4. 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
	NEK2	NM_002497.4	MANE Select	c.1320G>T	p.Gln440His	missense	Exon 8 of 8	NP_002488.1	P51955-1
	NEK2	NM_001204182.2		c.1111+3662G>T		intron	N/A	NP_001191111.1	F6U4U2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK2	ENST00000366999.9	TSL:1 MANE Select	c.1320G>T	p.Gln440His	missense	Exon 8 of 8	ENSP00000355966.4	P51955-1
	NEK2	ENST00000540251.5	TSL:1	c.1111+3662G>T		intron	N/A	ENSP00000440237.2	F6U4U2
	NEK2	ENST00000908300.1		c.1296G>T	p.Gln432His	missense	Exon 8 of 8	ENSP00000578359.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.74
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.51
MutPred		0.25		Gain of sheet (P = 0.0266)
MVP		0.91
MPC		1.1
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.17
gMVP		0.32
Mutation Taster		=64/36	polymorphism

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: rs141984487; hg19: chr1-211836786;