14-96810668-C-G

Variant names:

• chr14-96810668-C-G
• rs722869
• NM_003384.3:c.-6+13221C>G

Variant summary

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

The NM_003384.3(VRK1):​c.-6+13221C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,124 control chromosomes in the GnomAD database, including 3,334 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 0.15 (3334 hom., cov: 31)
• Consequence: VRK1 NM_003384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.257
• Publications: 10 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 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.-6+13221C>G		intron	N/A	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.-6+13221C>G		intron	N/A	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.-6+13221C>G		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.-6+13221C>G		intron	N/A	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.-6+13221C>G		intron	N/A	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000915477.1		c.-6+13221C>G		intron	N/A	ENSP00000585536.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22946 AN: 152006 Hom.: 3318 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.157

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

GnomAD4 genome AF: 0.151 AC: 22991 AN: 152124 Hom.: 3334 Cov.: 31 AF XY: 0.160 AC XY: 11860 AN XY: 74350

African (AFR) AF: 0.109 AC: 4533 AN: 41518

American (AMR) AF: 0.292 AC: 4469 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.834 AC: 4305 AN: 5160

South Asian (SAS) AF: 0.183 AC: 883 AN: 4812

European-Finnish (FIN) AF: 0.138 AC: 1450 AN: 10540

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0952 AC: 6471 AN: 68004

Other (OTH) AF: 0.163 AC: 345 AN: 2114

Alfa AF: 0.0550 Hom.: 39

Bravo AF: 0.165

Asia WGS AF: 0.440 AC: 1527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.1
DANN	Benign	0.84
PhyloP100		-0.26
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: rs722869; hg19: chr14-97277005;