19-49010528-G-A

Variant names:

Variant summary

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

The NM_006666.3(RUVBL2):c.704G>A(p.Arg235His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,392,078 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 0.000030 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

RUVBL2
NM_006666.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.10

Publications

2 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, 0.851

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3 link	c.704G>A	p.Arg235His	missense_variant	Exon 9 of 15	ENST00000595090.6	NP_006657.1	Q9Y230-1
RUVBL2	NM_001321190.2 link	c.602G>A	p.Arg201His	missense_variant	Exon 9 of 15		NP_001308119.1	B3KNL2
RUVBL2	NM_001321191.1 link	c.569G>A	p.Arg190His	missense_variant	Exon 9 of 15		NP_001308120.1	Q9Y230-2
RUVBL2	NR_135578.2 link	n.718G>A		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUVBL2	ENST00000595090.6 link	c.704G>A	p.Arg235His	missense_variant	Exon 9 of 15	1	NM_006666.3	ENSP00000473172.1		Q9Y230-1

Frequencies

GnomAD3 genomes

AF:

0.0000298

AC:

AN:

134068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000167

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249408

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000874

AC:

AN:

1257924

Hom.:

Cov.:

AF XY:

0.00000481

AC XY:

AN XY:

624282

show subpopulations

African (AFR)

AF:

0.0000362

AC:

AN:

27648

American (AMR)

AF:

0.00

AC:

AN:

38802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18868

East Asian (EAS)

AF:

0.00

AC:

AN:

22014

South Asian (SAS)

AF:

0.00

AC:

AN:

84276

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00000819

AC:

AN:

976964

Other (OTH)

AF:

0.0000424

AC:

AN:

47160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000298

AC:

AN:

134154

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

63956

show subpopulations

African (AFR)

AF:

0.0000276

AC:

AN:

36190

American (AMR)

AF:

0.000167

AC:

AN:

11990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3344

East Asian (EAS)

AF:

0.00

AC:

AN:

3886

South Asian (SAS)

AF:

0.00

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64468

Other (OTH)

AF:

0.00

AC:

AN:

1910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000826

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.704G>A (p.R235H) alteration is located in exon 9 (coding exon 9) of the RUVBL2 gene. This alteration results from a G to A substitution at nucleotide position 704, causing the arginine (R) at amino acid position 235 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

D;.;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.5

M;.;.

PhyloP100

9.1

PrimateAI

Pathogenic

0.84

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.78

MutPred

0.65

Loss of methylation at K234 (P = 0.0616);.;.;

MVP

0.79

MPC

2.3

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.91

Mutation Taster

=28/72

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-49010528-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over