19-49015822-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RUVBL2
• BP4: Computational evidence support a benign effect (MetaRNN=0.19638708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUVBL2	NM_006666.3	c.1372G>A	p.Glu458Lys	missense_variant	15/15	ENST00000595090.6
RUVBL2	NM_001321190.2	c.1270G>A	p.Glu424Lys	missense_variant	15/15
RUVBL2	NM_001321191.1	c.1237G>A	p.Glu413Lys	missense_variant	15/15
RUVBL2	NR_135578.2	n.1386G>A		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUVBL2	ENST00000595090.6	c.1372G>A	p.Glu458Lys	missense_variant	15/15	1	NM_006666.3	P1

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The 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;