chr2-58084881-G-T

Variant names:

• chr2-58084881-G-T
• rs1322434643
• NM_006296.7:c.187G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006296.7(VRK2):​c.187G>T​(p.Glu63*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VRK2 NM_006296.7 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.24
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK2	NM_006296.7	c.187G>T	p.Glu63*	stop_gained, splice_region_variant	Exon 4 of 13	ENST00000340157.9	NP_006287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK2	ENST00000340157.9	c.187G>T	p.Glu63*	stop_gained, splice_region_variant	Exon 4 of 13	1	NM_006296.7	ENSP00000342381.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379202 Hom.: 0 Cov.: 23 AF XY: 0.00000145 AC XY: 1 AN XY: 687554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30122

American (AMR) AF: 0.00 AC: 0 AN: 37566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24538

East Asian (EAS) AF: 0.00 AC: 0 AN: 37814

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057836

Other (OTH) AF: 0.00 AC: 0 AN: 56938

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	54
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		8.2
Vest4		0.88, 0.93, 0.94, 0.85
GERP RS		5.9
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1322434643; hg19: chr2-58312016;