14-96869691-C-T

Variant names:

• chr14-96869691-C-T
• rs1957137
• NM_003384.3:c.1069-6339C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003384.3(VRK1):​c.1069-6339C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 151,846 control chromosomes in the GnomAD database, including 29,611 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 0.62 (29611 hom., cov: 31)
• Consequence: VRK1 NM_003384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80
• Publications: 1 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), Genomics England PanelApp, Ambry Genetics, G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	NM_003384.3	MANE Select	c.1069-6339C>T		intron	N/A	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.1069-6339C>T		intron	N/A	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.1069-6342C>T		intron	N/A	NP_001397982.1	A0A7P0T838

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	ENST00000216639.8	TSL:1 MANE Select	c.1069-6339C>T		intron	N/A	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.1069-6339C>T		intron	N/A	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000679462.1		c.1069-6304C>T		intron	N/A	ENSP00000506011.1	A0A7P0TAA6

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93521 AN: 151728 Hom.: 29588 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.609

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.608

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.616 AC: 93584 AN: 151846 Hom.: 29611 Cov.: 31 AF XY: 0.613 AC XY: 45500 AN XY: 74220

African (AFR) AF: 0.664 AC: 27474 AN: 41396

American (AMR) AF: 0.526 AC: 8037 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3470

East Asian (EAS) AF: 0.156 AC: 804 AN: 5158

South Asian (SAS) AF: 0.604 AC: 2903 AN: 4810

European-Finnish (FIN) AF: 0.610 AC: 6414 AN: 10510

Middle Eastern (MID) AF: 0.593 AC: 172 AN: 290

European-Non Finnish (NFE) AF: 0.644 AC: 43771 AN: 67916

Other (OTH) AF: 0.602 AC: 1270 AN: 2108

Alfa AF: 0.464 Hom.: 1068

Bravo AF: 0.610

Asia WGS AF: 0.429 AC: 1492 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.95
DANN	Benign	0.18
PhyloP100		-2.8
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: rs1957137; hg19: chr14-97336028;