19-49010582-G-C

Variant names:

• chr19-49010582-G-C
• NM_006666.3:c.758G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006666.3(RUVBL2):​c.758G>C​(p.Arg253Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,560 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.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RUVBL2 NM_006666.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3	c.758G>C	p.Arg253Pro	missense_variant	Exon 9 of 15	ENST00000595090.6	NP_006657.1
RUVBL2	NM_001321190.2	c.656G>C	p.Arg219Pro	missense_variant	Exon 9 of 15		NP_001308119.1
RUVBL2	NM_001321191.1	c.623G>C	p.Arg208Pro	missense_variant	Exon 9 of 15		NP_001308120.1
RUVBL2	NR_135578.2	n.772G>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	c.758G>C	p.Arg253Pro	missense_variant	Exon 9 of 15	1	NM_006666.3	ENSP00000473172.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447560 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 719804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.7	H;.;.
PrimateAI	Pathogenic	0.86	D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.61		Loss of catalytic residue at R253 (P = 0.0146);.;.;
MVP		0.77
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr19-49513839;