1-211663488-C-CTTGA

Variant names:

• chr1-211663488-C-CTTGA
• NM_002497.4:c.1272_1275dupTCAA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002497.4(NEK2):​c.1272_1275dupTCAA​(p.Ala426SerfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEK2 NM_002497.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0471 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK2	NM_002497.4	c.1272_1275dupTCAA	p.Ala426SerfsTer7	frameshift_variant	Exon 8 of 8	ENST00000366999.9	NP_002488.1
NEK2	NM_001204182.2	c.1111+3614_1111+3617dupTCAA		intron_variant	Intron 7 of 7		NP_001191111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK2	ENST00000366999.9	c.1272_1275dupTCAA	p.Ala426SerfsTer7	frameshift_variant	Exon 8 of 8	1	NM_002497.4	ENSP00000355966.4
NEK2	ENST00000540251.5	c.1111+3614_1111+3617dupTCAA		intron_variant	Intron 7 of 7	1		ENSP00000440237.2
NEK2	ENST00000462283.5	n.712_715dupTCAA		non_coding_transcript_exon_variant	Exon 5 of 5	2
NEK2	ENST00000489633.1	n.*33_*36dupTCAA		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change creates a premature translational stop signal (p.Ala426Serfs*7) in the NEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the NEK2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEK2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-211836830;