rs398122961

Variant names:

• chr1-211671216-CTCATACA-T
• rs398122961
• NM_002497.4:c.617_624delTGTATGAGinsA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002497.4(NEK2):​c.617_624delTGTATGAGinsA​(p.Leu206HisfsTer5) variant causes a frameshift, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEK2 NM_002497.4 frameshift, synonymous
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.99
• Publications: 3 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-211671216-CTCATACA-T is Pathogenic according to our data. Variant chr1-211671216-CTCATACA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 91391.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK2	NM_002497.4	c.617_624delTGTATGAGinsA	p.Leu206HisfsTer5	frameshift_variant, synonymous_variant	Exon 4 of 8	ENST00000366999.9	NP_002488.1
NEK2	NM_001204182.2	c.617_624delTGTATGAGinsA	p.Leu206HisfsTer5	frameshift_variant, synonymous_variant	Exon 4 of 8		NP_001191111.1
NEK2	NM_001204183.2	c.617_624delTGTATGAGinsA	p.Leu206HisfsTer5	frameshift_variant, synonymous_variant	Exon 4 of 7		NP_001191112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK2	ENST00000366999.9	c.617_624delTGTATGAGinsA	p.Leu206HisfsTer5	frameshift_variant, synonymous_variant	Exon 4 of 8	1	NM_002497.4	ENSP00000355966.4
NEK2	ENST00000540251.5	c.617_624delTGTATGAGinsA	p.Leu206HisfsTer5	frameshift_variant, synonymous_variant	Exon 4 of 8	1		ENSP00000440237.2
NEK2	ENST00000366998.4	c.617_624delTGTATGAGinsA	p.Leu206HisfsTer5	frameshift_variant, synonymous_variant	Exon 4 of 7	1		ENSP00000355965.3
NEK2	ENST00000462283.5	n.62_69delTGTATGAGinsA		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 67 Pathogenic:1

Oct 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs398122961; hg19: chr1-211844558;