chr2-58123117-A-T

Variant names:

• chr2-58123117-A-T
• rs1677775232
• NM_006296.7:c.560A>T

Variant summary

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

The NM_006296.7(VRK2):​c.560A>T​(p.Tyr187Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,832 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y187C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VRK2 NM_006296.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK2	NM_006296.7	c.560A>T	p.Tyr187Phe	missense_variant	Exon 8 of 13	ENST00000340157.9	NP_006287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK2	ENST00000340157.9	c.560A>T	p.Tyr187Phe	missense_variant	Exon 8 of 13	1	NM_006296.7	ENSP00000342381.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447832 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719954

African (AFR) AF: 0.00 AC: 0 AN: 32146

American (AMR) AF: 0.0000244 AC: 1 AN: 41014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39012

South Asian (SAS) AF: 0.00 AC: 0 AN: 83078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108008

Other (OTH) AF: 0.00 AC: 0 AN: 59870

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.64	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.37	N;N;N;.;N;.
PhyloP100		9.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	.;D;D;.;D;D
REVEL	Benign	0.26
Sift	Benign	0.31	.;T;T;.;T;T
Sift4G	Benign	0.18	.;T;T;T;T;T
Polyphen		0.98	D;P;P;.;P;.
Vest4		0.68, 0.65, 0.66, 0.66, 0.67
MutPred		0.68		Loss of phosphorylation at Y187 (P = 0.0795);Loss of phosphorylation at Y187 (P = 0.0795);Loss of phosphorylation at Y187 (P = 0.0795);.;Loss of phosphorylation at Y187 (P = 0.0795);.;
MVP		0.61
MPC		0.11
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.81
Mutation Taster		=56/44	polymorphism

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: rs1677775232; hg19: chr2-58350252; COSMIC: COSV60878407;