14-96852823-G-C

Variant names:

• chr14-96852823-G-C
• rs191021502
• NM_003384.3:c.375-8G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003384.3(VRK1):​c.375-8G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0012 in 1,609,988 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: VRK1 NM_003384.3 splice_region, intron
• Scores: Splicing: ADA: 0.0009403
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.22
• Publications: 0 publications found

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]

VRK1 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 1A

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp
• microcephaly-complex motor and sensory axonal neuropathy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 14-96852823-G-C is Benign according to our data. Variant chr14-96852823-G-C is described in ClinVar as Benign. ClinVar VariationId is 315122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000894 (136/152094) while in subpopulation SAS AF = 0.012 (58/4820). AF 95% confidence interval is 0.00956. There are 1 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	NM_003384.3	MANE Select	c.375-8G>C		splice_region intron	N/A	NP_003375.1
	VRK1	NM_001411051.1		c.375-8G>C		splice_region intron	N/A	NP_001397980.1
	VRK1	NM_001411053.1		c.375-8G>C		splice_region intron	N/A	NP_001397982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	ENST00000216639.8	TSL:1 MANE Select	c.375-8G>C		splice_region intron	N/A	ENSP00000216639.3
	VRK1	ENST00000679770.1		c.375-8G>C		splice_region intron	N/A	ENSP00000505214.1
	VRK1	ENST00000679462.1		c.375-8G>C		splice_region intron	N/A	ENSP00000506011.1

Frequencies

GnomAD3 genomes AF: 0.000895 AC: 136 AN: 151976 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00188 AC: 471 AN: 250846 AF XY: 0.00237

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00124 AC: 1803 AN: 1457894 Hom.: 15 Cov.: 30 AF XY: 0.00151 AC XY: 1096 AN XY: 725548

African (AFR) AF: 0.0000599 AC: 2 AN: 33400

American (AMR) AF: 0.000537 AC: 24 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 44 AN: 26104

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39618

South Asian (SAS) AF: 0.0114 AC: 982 AN: 86140

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53322

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5750

European-Non Finnish (NFE) AF: 0.000595 AC: 660 AN: 1108576

Other (OTH) AF: 0.00131 AC: 79 AN: 60280

GnomAD4 genome AF: 0.000894 AC: 136 AN: 152094 Hom.: 1 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74328

African (AFR) AF: 0.0000963 AC: 4 AN: 41516

American (AMR) AF: 0.00164 AC: 25 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4820

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10582

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67954

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.000548

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000949

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 10, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Pontocerebellar hypoplasia type 1A Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Congenital pontocerebellar hypoplasia type 1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		4.2
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00094
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.050		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: rs191021502; hg19: chr14-97319160;