rs2145635

chr14-96833516-A-Gchr14-96833516-A-T

Variant summary

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

The NM_003384.3(VRK1):c.45A>G(p.Ala15=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,613,514 control chromosomes in the GnomAD database, including 116,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8727 hom., cov: 33)
  • Exomes 𝑓: 0.38 (107522 hom.)
• Consequence: VRK1 NM_003384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.762

Genes affected

VRK1 (HGNC:12718): (VRK serine/threonine kinase 1) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. This gene is widely expressed in human tissues and has increased expression in actively dividing cells, such as those in testis, thymus, fetal liver, and carcinomas. Its protein localizes to the nucleus and has been shown to promote the stability and nuclear accumulation of a transcriptionally active p53 molecule and, in vitro, to phosphorylate Thr18 of p53 and reduce p53 ubiquitination. This gene, therefore, may regulate cell proliferation. This protein also phosphorylates histone, casein, and the transcription factors ATF2 (activating transcription factor 2) and c-JUN. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-96833516-A-G is Benign according to our data. Variant chr14-96833516-A-G is described in ClinVar as [Benign]. Clinvar id is 130731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-96833516-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.762 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VRK1	NM_003384.3	c.45A>G	p.Ala15=	synonymous_variant	2/13	ENST00000216639.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VRK1	ENST00000216639.8	c.45A>G	p.Ala15=	synonymous_variant	2/13	1	NM_003384.3	P4

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49639 AN: 152006 Hom.: 8729 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.356 AC: 89305 AN: 251022 Hom.: 16884 AF XY: 0.366 AC XY: 49684 AN XY: 135654

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.425

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.378 AC: 553130 AN: 1461390 Hom.: 107522 Cov.: 51 AF XY: 0.381 AC XY: 276643 AN XY: 727000

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.354

Gnomad4 ASJ exome AF: 0.309

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.326 AC: 49657 AN: 152124 Hom.: 8727 Cov.: 33 AF XY: 0.331 AC XY: 24636 AN XY: 74358

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.390

Gnomad4 OTH AF: 0.321

Alfa AF: 0.373 Hom.: 12559

Bravo AF: 0.315

Asia WGS AF: 0.256 AC: 889 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.383

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 1A Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Isolated microphthalmia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	4.7
Dann	Benign	0.46

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: rs2145635; hg19: chr14-97299853; COSMIC: COSV53709280;