chr1-211673534-A-G

Position:

• chr1-211673534-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002497.4(NEK2):​c.504T>C​(p.His168His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,613,692 control chromosomes in the GnomAD database, including 215,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22444 hom., cov: 33)
  • Exomes 𝑓: 0.51 (192719 hom.)
• Consequence: NEK2 NM_002497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.573

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-211673534-A-G is Benign according to our data. Variant chr1-211673534-A-G is described in ClinVar as [Benign]. Clinvar id is 403228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.573 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK2	NM_002497.4	c.504T>C	p.His168His	synonymous_variant	3/8	ENST00000366999.9	NP_002488.1
NEK2	NM_001204182.2	c.504T>C	p.His168His	synonymous_variant	3/8		NP_001191111.1
NEK2	NM_001204183.2	c.504T>C	p.His168His	synonymous_variant	3/7		NP_001191112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK2	ENST00000366999.9	c.504T>C	p.His168His	synonymous_variant	3/8	1	NM_002497.4	ENSP00000355966.4
NEK2	ENST00000540251.5	c.504T>C	p.His168His	synonymous_variant	3/8	1		ENSP00000440237.2
NEK2	ENST00000366998.4	c.504T>C	p.His168His	synonymous_variant	3/7	1		ENSP00000355965.3

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81766 AN: 151964 Hom.: 22412 Cov.: 33

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.538

GnomAD3 exomes AF: 0.567 AC: 142349 AN: 251222 Hom.: 41957 AF XY: 0.563 AC XY: 76411 AN XY: 135802

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.733

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.729

Gnomad SAS exome AF: 0.632

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.481

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.508 AC: 742295 AN: 1461608 Hom.: 192719 Cov.: 49 AF XY: 0.511 AC XY: 371273 AN XY: 727116

Gnomad4 AFR exome AF: 0.535

Gnomad4 AMR exome AF: 0.721

Gnomad4 ASJ exome AF: 0.485

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.628

Gnomad4 FIN exome AF: 0.580

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.520

GnomAD4 genome AF: 0.538 AC: 81846 AN: 152084 Hom.: 22444 Cov.: 33 AF XY: 0.545 AC XY: 40522 AN XY: 74332

Gnomad4 AFR AF: 0.540

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.730

Gnomad4 SAS AF: 0.631

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.488

Gnomad4 OTH AF: 0.545

Alfa AF: 0.507 Hom.: 9110

Bravo AF: 0.541

Asia WGS AF: 0.665 AC: 2309 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.480

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Retinitis pigmentosa 67 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.080
DANN	Benign	0.53

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: rs701929; hg19: chr1-211846876; COSMIC: COSV65357449; COSMIC: COSV65357449;