Genetic Variant RUVBL2:p.Val249Ile (chr19-49010569-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006666.3(RUVBL2):c.745G>A(p.Val249Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,592,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RUVBL2
NM_006666.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.25

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.399732).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3 link	c.745G>A	p.Val249Ile	missense_variant	Exon 9 of 15	ENST00000595090.6	NP_006657.1	Q9Y230-1
RUVBL2	NM_001321190.2 link	c.643G>A	p.Val215Ile	missense_variant	Exon 9 of 15		NP_001308119.1	B3KNL2
RUVBL2	NM_001321191.1 link	c.610G>A	p.Val204Ile	missense_variant	Exon 9 of 15		NP_001308120.1	Q9Y230-2
RUVBL2	NR_135578.2 link	n.759G>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.745G>A	p.Val249Ile	missense_variant	Exon 9 of 15	1	NM_006666.3	ENSP00000473172.1		Q9Y230-1

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

149966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000609

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000444

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000361

AC:

AN:

249438

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1442392

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

717234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32858

American (AMR)

AF:

0.00

AC:

AN:

44028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25424

East Asian (EAS)

AF:

0.0000785

AC:

AN:

38228

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.0000173

AC:

AN:

1099260

Other (OTH)

AF:

0.0000339

AC:

AN:

58958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000467

AC:

AN:

149966

Hom.:

Cov.:

AF XY:

0.0000684

AC XY:

AN XY:

73140

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40762

American (AMR)

AF:

0.00

AC:

AN:

14950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.000609

AC:

AN:

4928

South Asian (SAS)

AF:

0.00

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000444

AC:

AN:

67624

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.745G>A (p.V249I) 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 745, causing the valine (V) at amino acid position 249 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.78

Sift4G

Benign

0.13

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.61

MutPred

0.59

Gain of helix (P = 0.0082);.;.;

MVP

0.64

MPC

1.6

ClinPred

0.80

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.70

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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19-49010569-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over