chr13-52135802-A-C

Variant names:

• chr13-52135802-A-C
• rs2296351
• NM_002498.3:c.1236T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002498.3(NEK3):​c.1236T>G​(p.Pro412Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,613,036 control chromosomes in the GnomAD database, including 102,043 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (7008 hom., cov: 32)
  • Exomes 𝑓: 0.35 (95035 hom.)
• Consequence: NEK3 NM_002498.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.395

Genes affected

NEK3 (HGNC:7746): (NIMA related kinase 3) This gene encodes a member of the NimA (never in mitosis A) family of serine/threonine protein kinases. The encoded protein differs from other NimA family members in that it is not cell cycle regulated and is found primarily in the cytoplasm. The kinase is activated by prolactin stimulation, leading to phosphorylation of VAV2 guanine nucleotide exchange factor, paxillin, and activation of the RAC1 GTPase. Two functional alleles for this gene have been identified in humans. The reference genome assembly (GRCh38) represents a functional allele that is associated with the inclusion of an additional coding exon in protein-coding transcripts, compared to an alternate functional allele that lacks the exon. [provided by RefSeq, Sep 2019]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP7: Synonymous conserved (PhyloP=-0.395 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK3	NM_002498.3	c.1236T>G	p.Pro412Pro	synonymous_variant	Exon 14 of 16	ENST00000610828.5	NP_002489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK3	ENST00000610828.5	c.1236T>G	p.Pro412Pro	synonymous_variant	Exon 14 of 16	1	NM_002498.3	ENSP00000480328.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41451 AN: 151998 Hom.: 7012 Cov.: 32

Gnomad AFR AF: 0.0681

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.305 AC: 75954 AN: 248640 AF XY: 0.307

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.352 AC: 514816 AN: 1460920 Hom.: 95035 Cov.: 34 AF XY: 0.348 AC XY: 253100 AN XY: 726790

Gnomad4 AFR exome AF: 0.0572 AC: 1913 AN: 33468

Gnomad4 AMR exome AF: 0.287 AC: 12841 AN: 44702

Gnomad4 ASJ exome AF: 0.381 AC: 9947 AN: 26120

Gnomad4 EAS exome AF: 0.187 AC: 7437 AN: 39678

Gnomad4 SAS exome AF: 0.191 AC: 16450 AN: 86224

Gnomad4 FIN exome AF: 0.369 AC: 19670 AN: 53338

Gnomad4 NFE exome AF: 0.382 AC: 424155 AN: 1111276

Gnomad4 Remaining exome AF: 0.344 AC: 20768 AN: 60346

GnomAD4 genome AF: 0.272 AC: 41439 AN: 152116 Hom.: 7008 Cov.: 32 AF XY: 0.269 AC XY: 20025 AN XY: 74358

Gnomad4 AFR AF: 0.0679 AC: 0.0679006 AN: 0.0679006

Gnomad4 AMR AF: 0.320 AC: 0.32017 AN: 0.32017

Gnomad4 ASJ AF: 0.374 AC: 0.373918 AN: 0.373918

Gnomad4 EAS AF: 0.198 AC: 0.198223 AN: 0.198223

Gnomad4 SAS AF: 0.176 AC: 0.175642 AN: 0.175642

Gnomad4 FIN AF: 0.356 AC: 0.356495 AN: 0.356495

Gnomad4 NFE AF: 0.379 AC: 0.379313 AN: 0.379313

Gnomad4 OTH AF: 0.322 AC: 0.321801 AN: 0.321801

Alfa AF: 0.327 Hom.: 11106

Bravo AF: 0.264

Asia WGS AF: 0.162 AC: 563 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.377

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.83
DANN	Benign	0.39
Mutation Taster		=99/1	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

Publications

LitVar

Other links and lift over

dbSNP: rs2296351; hg19: chr13-52709938; COSMIC: COSV51616106; COSMIC: COSV51616106;