Genetic Variant RUVBL2:p.Val225Met (chr19-49010497-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_006666.3(RUVBL2):c.673G>A(p.Val225Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000648 in 693,914 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V225A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

RUVBL2
NM_006666.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

Publications

1 publications found

Variant links:

Genes affected

RUVBL2 (HGNC:10475): (RuvB like AAA ATPase 2) This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. Functional analysis showed that this gene product has both ATPase and DNA helicase activities. This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation. [provided by RefSeq, Jul 2008]

RUVBL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

BS2

High AC in GnomAdExome4 at 41 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006666.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUVBL2	NM_006666.3	MANE Select	c.673G>A	p.Val225Met	missense	Exon 9 of 15	NP_006657.1	Q9Y230-1
RUVBL2	NM_001321190.2		c.571G>A	p.Val191Met	missense	Exon 9 of 15	NP_001308119.1	B3KNL2
RUVBL2	NM_001321191.1		c.538G>A	p.Val180Met	missense	Exon 9 of 15	NP_001308120.1	Q9Y230-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUVBL2	ENST00000595090.6	TSL:1 MANE Select	c.673G>A	p.Val225Met	missense	Exon 9 of 15	ENSP00000473172.1	Q9Y230-1
RUVBL2	ENST00000221413.10	TSL:1	n.662G>A		non_coding_transcript_exon	Exon 9 of 15	ENSP00000221413.6	X6R2L4
RUVBL2	ENST00000888169.1		c.694G>A	p.Val232Met	missense	Exon 9 of 15	ENSP00000558228.1

Frequencies

GnomAD3 genomes

AF:

0.0000364

AC:

AN:

109964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000301

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000170

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000563

AC:

AN:

248614

AF XY:

0.0000815

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000702

AC:

AN:

583950

Hom.:

Cov.:

AF XY:

0.0000878

AC XY:

AN XY:

307662

show subpopulations

African (AFR)

AF:

0.0000685

AC:

AN:

14606

American (AMR)

AF:

0.0000271

AC:

AN:

36862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13706

East Asian (EAS)

AF:

0.00

AC:

AN:

15852

South Asian (SAS)

AF:

0.000255

AC:

AN:

70658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3308

European-Non Finnish (NFE)

AF:

0.0000485

AC:

AN:

371290

Other (OTH)

AF:

0.000126

AC:

AN:

23842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000364

AC:

AN:

109964

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

50070

show subpopulations

African (AFR)

AF:

0.0000359

AC:

AN:

27838

American (AMR)

AF:

0.000138

AC:

AN:

7252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3124

East Asian (EAS)

AF:

0.000301

AC:

AN:

3326

South Asian (SAS)

AF:

0.00

AC:

AN:

3072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.0000170

AC:

AN:

58964

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ExAC

AF:

0.0000744

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.2

PhyloP100

6.1

PrimateAI

Pathogenic

0.88

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.81

MVP

0.76

MPC

1.5

ClinPred

0.95

GERP RS

4.9

Varity_R

0.79

gMVP

0.87

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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