2-58131870-A-T

Variant names:

• chr2-58131870-A-T
• rs762051577
• NM_006296.7:c.739A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006296.7(VRK2):​c.739A>T​(p.Lys247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: VRK2 NM_006296.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

Genes affected

VRK2 (HGNC:12719): (VRK serine/threonine kinase 2) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. The encoded protein acts as an effector of signaling pathways that regulate apoptosis and tumor cell growth. Variants in this gene have been associated with schizophrenia. Alternative splicing results in multiple transcript variants that differ in their subcellular localization and biological activity. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006296.7. 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
	VRK2	NM_006296.7	MANE Select	c.739A>T	p.Lys247*	stop_gained	Exon 9 of 13	NP_006287.2	Q86Y07-1
	VRK2	NM_001130480.2		c.739A>T	p.Lys247*	stop_gained	Exon 9 of 13	NP_001123952.1	Q86Y07-1
	VRK2	NM_001130481.2		c.739A>T	p.Lys247*	stop_gained	Exon 9 of 13	NP_001123953.1	Q86Y07-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK2	ENST00000340157.9	TSL:1 MANE Select	c.739A>T	p.Lys247*	stop_gained	Exon 9 of 13	ENSP00000342381.4	Q86Y07-1
	VRK2	ENST00000435505.6	TSL:1	c.739A>T	p.Lys247*	stop_gained	Exon 12 of 16	ENSP00000408002.2	Q86Y07-1
	VRK2	ENST00000440705.6	TSL:1	c.670A>T	p.Lys224*	stop_gained	Exon 9 of 13	ENSP00000398323.2	Q86Y07-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.68	D
PhyloP100		1.9
Vest4		0.89
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762051577; hg19: chr2-58359005;