2-58089649-A-C

Variant names:

• chr2-58089649-A-C
• rs910273959
• NM_006296.7:c.469A>C

Variant summary

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

The NM_006296.7(VRK2):​c.469A>C​(p.Ile157Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,450,582 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I157V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: VRK2 NM_006296.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92
• 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=0.41203374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK2	NM_006296.7	c.469A>C	p.Ile157Leu	missense_variant	Exon 7 of 13	ENST00000340157.9	NP_006287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK2	ENST00000340157.9	c.469A>C	p.Ile157Leu	missense_variant	Exon 7 of 13	1	NM_006296.7	ENSP00000342381.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1450582 Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3 AN XY: 721884

⚠️ 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: 33232

American (AMR) AF: 0.00 AC: 0 AN: 42896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 84910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105078

Other (OTH) AF: 0.00 AC: 0 AN: 60032

⚠️ 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469A>C (p.I157L) alteration is located in exon 7 (coding exon 6) of the VRK2 gene. This alteration results from a A to C substitution at nucleotide position 469, causing the isoleucine (I) at amino acid position 157 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	.;T;.;.;T;.
Eigen	Benign	-0.0082
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;.;T;T;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.41	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N;N;N;.;N;.
PhyloP100		4.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	.;N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.099	.;T;T;.;T;T
Sift4G	Benign	0.24	.;T;T;T;T;T
Polyphen		0.0030	B;B;B;.;B;.
Vest4		0.33, 0.36, 0.40, 0.36, 0.33
MutPred		0.46		Gain of catalytic residue at I157 (P = 0.0458);Gain of catalytic residue at I157 (P = 0.0458);Gain of catalytic residue at I157 (P = 0.0458);.;Gain of catalytic residue at I157 (P = 0.0458);.;
MVP		0.28
MPC		0.020
ClinPred		0.71	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.72
Mutation Taster		=49/51	disease causing

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: rs910273959; hg19: chr2-58316784;