Genetic Variant RUVBL2:p.Val225Leu (chr19-49010497-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006666.3(RUVBL2):c.673G>C(p.Val225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 583,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V225M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RUVBL2
NM_006666.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3 link	c.673G>C	p.Val225Leu	missense_variant	Exon 9 of 15	ENST00000595090.6	NP_006657.1	Q9Y230-1
RUVBL2	NM_001321190.2 link	c.571G>C	p.Val191Leu	missense_variant	Exon 9 of 15		NP_001308119.1	B3KNL2
RUVBL2	NM_001321191.1 link	c.538G>C	p.Val180Leu	missense_variant	Exon 9 of 15		NP_001308120.1	Q9Y230-2
RUVBL2	NR_135578.2 link	n.687G>C		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.673G>C	p.Val225Leu	missense_variant	Exon 9 of 15	1	NM_006666.3	ENSP00000473172.1		Q9Y230-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248614

AF XY:

0.0000222

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:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

583952

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

307664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14606

American (AMR)

AF:

0.00

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:

0.00

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:

0.0000108

AC:

AN:

371292

Other (OTH)

AF:

0.00

AC:

AN:

23842

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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.060

MutationAssessor

Uncertain

2.9

M;.;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.87

Sift4G

Benign

0.065

T;T;T

Polyphen

0.94

P;.;.

Vest4

0.79

MutPred

0.88

Gain of ubiquitination at K223 (P = 0.1093);.;.;

MVP

0.77

MPC

1.7

ClinPred

0.94

GERP RS

4.9

Varity_R

0.54

gMVP

0.86

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over