2-58123192-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_006296.7(VRK2):c.635G>A(p.Gly212Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,590,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )
Consequence
VRK2
NM_006296.7 missense
NM_006296.7 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VRK2 | NM_006296.7 | c.635G>A | p.Gly212Glu | missense_variant | 8/13 | ENST00000340157.9 | NP_006287.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VRK2 | ENST00000340157.9 | c.635G>A | p.Gly212Glu | missense_variant | 8/13 | 1 | NM_006296.7 | ENSP00000342381 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000659 AC: 15AN: 227490Hom.: 0 AF XY: 0.0000487 AC XY: 6AN XY: 123284
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GnomAD4 exome AF: 0.0000535 AC: 77AN: 1438830Hom.: 0 Cov.: 30 AF XY: 0.0000447 AC XY: 32AN XY: 715570
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | The c.635G>A (p.G212E) alteration is located in exon 8 (coding exon 7) of the VRK2 gene. This alteration results from a G to A substitution at nucleotide position 635, causing the glycine (G) at amino acid position 212 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;H;H;.;H;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;D;.;D;D
REVEL
Uncertain
Sift
Pathogenic
.;D;D;.;D;D
Sift4G
Pathogenic
.;D;D;D;D;D
Polyphen
D;D;D;.;D;.
Vest4
1.0, 0.99, 0.99, 0.99
MutPred
Gain of catalytic residue at G212 (P = 0.0519);Gain of catalytic residue at G212 (P = 0.0519);Gain of catalytic residue at G212 (P = 0.0519);.;Gain of catalytic residue at G212 (P = 0.0519);.;
MVP
0.71
MPC
0.11
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at