rs772731615

Variant names:

• chr14-96860628-C-T
• rs772731615
• NM_003384.3:c.961C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_003384.3(VRK1):​c.961C>T​(p.Arg321Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000820501: Experimental studies have shown that this missense change affects VRK1 function (PMID:31527692)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: VRK1 NM_003384.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 2.46
• Publications: 10 publications found

Genes affected

VRK1 (HGNC:12718): (VRK serine/threonine kinase 1) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. This gene is widely expressed in human tissues and has increased expression in actively dividing cells, such as those in testis, thymus, fetal liver, and carcinomas. Its protein localizes to the nucleus and has been shown to promote the stability and nuclear accumulation of a transcriptionally active p53 molecule and, in vitro, to phosphorylate Thr18 of p53 and reduce p53 ubiquitination. This gene, therefore, may regulate cell proliferation. This protein also phosphorylates histone, casein, and the transcription factors ATF2 (activating transcription factor 2) and c-JUN. [provided by RefSeq, Jul 2008]

VRK1 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 1A

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
• microcephaly-complex motor and sensory axonal neuropathy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000820501: Experimental studies have shown that this missense change affects VRK1 function (PMID: 31527692).; SCV000535254: Published functional studies demonstrate a damaging effect, as the R321C variant results in reduced kinase activity (Martn-Doncel et al., 2019); PMID:24088041
• PP5: Variant 14-96860628-C-T is Pathogenic according to our data. Variant chr14-96860628-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 209205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003384.3. 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
	VRK1	NM_003384.3	MANE Select	c.961C>T	p.Arg321Cys	missense	Exon 11 of 13	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.961C>T	p.Arg321Cys	missense	Exon 11 of 14	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.961C>T	p.Arg321Cys	missense	Exon 11 of 13	NP_001397982.1	A0A7P0T838

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	ENST00000216639.8	TSL:1 MANE Select	c.961C>T	p.Arg321Cys	missense	Exon 11 of 13	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.961C>T	p.Arg321Cys	missense	Exon 11 of 14	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000679462.1		c.961C>T	p.Arg321Cys	missense	Exon 10 of 12	ENSP00000506011.1	A0A7P0TAA6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 250920 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000898

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1460922 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00105 AC: 47 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111448

Other (OTH) AF: 0.000116 AC: 7 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000231 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Pontocerebellar hypoplasia type 1A (3)
1	-	-	Juvenile amyotrophic lateral sclerosis (1)
1	-	-	not provided (1)
1	-	-	Pontocerebellar hypoplasia type 1A;C5882703:Neuronopathy, distal hereditary motor, autosomal recessive 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.046	D
Polyphen		0.50	P
Vest4		0.85
MutPred		0.62		Gain of catalytic residue at Q326 (P = 0.1045)
MVP		0.49
MPC		0.44
ClinPred		0.36	T
GERP RS		5.1
Varity_R		0.64
gMVP		0.68
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs772731615; hg19: chr14-97326965; COSMIC: COSV53710603;