dbSNP rs147853760: VRK1:p.Asp340Asp (chr14-96860687-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS1

The NM_003384.3(VRK1):c.1020C>T(p.Asp340Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,613,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

VRK1
NM_003384.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 1.00

Publications

1 publications found

Variant links:

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

VRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.068).

BP6

Variant 14-96860687-C-T is Benign according to our data. Variant chr14-96860687-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378856.

BP7

Synonymous conserved (PhyloP=1 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000688 (1005/1461094) while in subpopulation MID AF = 0.00573 (33/5760). AF 95% confidence interval is 0.00419. There are 1 homozygotes in GnomAdExome4. There are 496 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VRK1	NM_003384.3	MANE Select	c.1020C>T	p.Asp340Asp	synonymous	Exon 11 of 13	NP_003375.1	Q99986
VRK1	NM_001411051.1		c.1020C>T	p.Asp340Asp	synonymous	Exon 11 of 14	NP_001397980.1	H0YJF7
VRK1	NM_001411053.1		c.1020C>T	p.Asp340Asp	synonymous	Exon 11 of 13	NP_001397982.1	A0A7P0T838

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VRK1	ENST00000216639.8	TSL:1 MANE Select	c.1020C>T	p.Asp340Asp	synonymous	Exon 11 of 13	ENSP00000216639.3	Q99986
VRK1	ENST00000679770.1		c.1020C>T	p.Asp340Asp	synonymous	Exon 11 of 14	ENSP00000505214.1	A0A7P0Z445
VRK1	ENST00000679462.1		c.1020C>T	p.Asp340Asp	synonymous	Exon 10 of 12	ENSP00000506011.1	A0A7P0TAA6

Frequencies

GnomAD3 genomes

AF:

0.000684

AC:

104

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000824

AC:

207

AN:

251124

AF XY:

0.000766

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000811

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000688

AC:

1005

AN:

1461094

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

496

AN XY:

726874

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33450

American (AMR)

AF:

0.00195

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00307

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00573

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000608

AC:

676

AN:

1111548

Other (OTH)

AF:

0.00174

AC:

105

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000671

AC:

102

AN:

152118

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41532

American (AMR)

AF:

0.00183

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

67950

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000960

EpiCase

AF:

0.00104

EpiControl

AF:

0.00125

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Pontocerebellar hypoplasia type 1A (3)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

5.0

(source)

DANN

Benign

0.37

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over