chr1-211663447-T-C

Variant names:

• chr1-211663447-T-C
• rs12031285
• NM_002497.4:c.1317A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002497.4(NEK2):​c.1317A>G​(p.Arg439Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,612,166 control chromosomes in the GnomAD database, including 51,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6530 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44960 hom.)
• Consequence: NEK2 NM_002497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.01
• Publications: 15 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-211663447-T-C is Benign according to our data. Variant chr1-211663447-T-C is described in ClinVar as Benign. ClinVar VariationId is 403226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

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.1317A>G	p.Arg439Arg	synonymous	Exon 8 of 8	NP_002488.1	P51955-1
	NEK2	NM_001204182.2		c.1111+3659A>G		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.1317A>G	p.Arg439Arg	synonymous	Exon 8 of 8	ENSP00000355966.4	P51955-1
	NEK2	ENST00000540251.5	TSL:1	c.1111+3659A>G		intron	N/A	ENSP00000440237.2	F6U4U2
	NEK2	ENST00000908300.1		c.1293A>G	p.Arg431Arg	synonymous	Exon 8 of 8	ENSP00000578359.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43271 AN: 151988 Hom.: 6510 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.268 AC: 66655 AN: 248272 AF XY: 0.262

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.273

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.245 AC: 357711 AN: 1460060 Hom.: 44960 Cov.: 37 AF XY: 0.245 AC XY: 177565 AN XY: 726172

African (AFR) AF: 0.376 AC: 12586 AN: 33458

American (AMR) AF: 0.349 AC: 15521 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5658 AN: 26102

East Asian (EAS) AF: 0.272 AC: 10796 AN: 39680

South Asian (SAS) AF: 0.281 AC: 24170 AN: 85968

European-Finnish (FIN) AF: 0.259 AC: 13801 AN: 53310

Middle Eastern (MID) AF: 0.219 AC: 1257 AN: 5752

European-Non Finnish (NFE) AF: 0.233 AC: 258612 AN: 1110986

Other (OTH) AF: 0.254 AC: 15310 AN: 60310

GnomAD4 genome AF: 0.285 AC: 43342 AN: 152106 Hom.: 6530 Cov.: 32 AF XY: 0.284 AC XY: 21132 AN XY: 74362

African (AFR) AF: 0.370 AC: 15338 AN: 41460

American (AMR) AF: 0.319 AC: 4880 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 727 AN: 3472

East Asian (EAS) AF: 0.260 AC: 1346 AN: 5170

South Asian (SAS) AF: 0.299 AC: 1443 AN: 4822

European-Finnish (FIN) AF: 0.247 AC: 2609 AN: 10580

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16083 AN: 68008

Other (OTH) AF: 0.277 AC: 584 AN: 2110

Alfa AF: 0.253 Hom.: 2181

Bravo AF: 0.292

Asia WGS AF: 0.325 AC: 1130 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.67
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs12031285; hg19: chr1-211836789; COSMIC: COSV65357282; COSMIC: COSV65357282;