chr19-49015822-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006666.3(RUVBL2):​c.1372G>A​(p.Glu458Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 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: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RUVBL2
NM_006666.3 missense

Scores

2
2
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19638708).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RUVBL2NM_006666.3 linkuse as main transcriptc.1372G>A p.Glu458Lys missense_variant 15/15 ENST00000595090.6
RUVBL2NM_001321190.2 linkuse as main transcriptc.1270G>A p.Glu424Lys missense_variant 15/15
RUVBL2NM_001321191.1 linkuse as main transcriptc.1237G>A p.Glu413Lys missense_variant 15/15
RUVBL2NR_135578.2 linkuse as main transcriptn.1386G>A non_coding_transcript_exon_variant 15/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RUVBL2ENST00000595090.6 linkuse as main transcriptc.1372G>A p.Glu458Lys missense_variant 15/151 NM_006666.3 P1Q9Y230-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461856
Hom.:
0
Cov.:
50
AF XY:
0.00000138
AC XY:
1
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 20, 2021The c.1372G>A (p.E458K) alteration is located in exon 15 (coding exon 15) of the RUVBL2 gene. This alteration results from a G to A substitution at nucleotide position 1372, causing the glutamic acid (E) at amino acid position 458 to be replaced by a lysine (K). 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
Benign
0.14
BayesDel_addAF
Benign
-0.071
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T
Eigen
Benign
0.0057
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.99
D;D
PrimateAI
Pathogenic
0.83
D
Sift4G
Benign
0.32
T
Polyphen
0.049
B
Vest4
0.35
MutPred
0.31
Gain of ubiquitination at E458 (P = 0.0042);
MVP
0.36
MPC
1.0
ClinPred
0.85
D
GERP RS
5.1
Varity_R
0.14
gMVP
0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49519079; COSMIC: COSV55484070; COSMIC: COSV55484070; API