chr2-58088442-G-A

Variant names:

• chr2-58088442-G-A
• rs768716776
• NM_006296.7:c.446G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006296.7(VRK2):​c.446G>A​(p.Arg149Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,600,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: VRK2 NM_006296.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29728687).

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.446G>A	p.Arg149Gln	missense	Exon 6 of 13	NP_006287.2	Q86Y07-1
	VRK2	NM_001130480.2		c.446G>A	p.Arg149Gln	missense	Exon 6 of 13	NP_001123952.1	Q86Y07-1
	VRK2	NM_001130481.2		c.446G>A	p.Arg149Gln	missense	Exon 6 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.446G>A	p.Arg149Gln	missense	Exon 6 of 13	ENSP00000342381.4	Q86Y07-1
	VRK2	ENST00000435505.6	TSL:1	c.446G>A	p.Arg149Gln	missense	Exon 9 of 16	ENSP00000408002.2	Q86Y07-1
	VRK2	ENST00000440705.6	TSL:1	c.377G>A	p.Arg126Gln	missense	Exon 6 of 13	ENSP00000398323.2	Q86Y07-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248606 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000221 AC: 32 AN: 1448430 Hom.: 0 Cov.: 27 AF XY: 0.0000194 AC XY: 14 AN XY: 721260

African (AFR) AF: 0.0000907 AC: 3 AN: 33086

American (AMR) AF: 0.00 AC: 0 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000254 AC: 28 AN: 1101344

Other (OTH) AF: 0.00 AC: 0 AN: 59922

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		4.2
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.21
Sift	Benign	0.37	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.66		Loss of MoRF binding (P = 0.0655)
MVP		0.36
MPC		0.11
ClinPred		0.72	D
GERP RS		5.6
Varity_R		0.47
gMVP		0.62
Mutation Taster		=65/35	polymorphism

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: rs768716776; hg19: chr2-58315577; COSMIC: COSV100418251; COSMIC: COSV100418251;