19-49007358-C-A

Position:

• chr19-49007358-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006666.3(RUVBL2):​c.452C>A​(p.Ala151Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A151T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUVBL2 NM_006666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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 2 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=0.40175283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUVBL2	NM_006666.3	c.452C>A	p.Ala151Glu	missense_variant	6/15	ENST00000595090.6
RUVBL2	NM_001321190.2	c.350C>A	p.Ala117Glu	missense_variant	6/15
RUVBL2	NM_001321191.1	c.317C>A	p.Ala106Glu	missense_variant	6/15
RUVBL2	NR_135578.2	n.477C>A		non_coding_transcript_exon_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUVBL2	ENST00000595090.6	c.452C>A	p.Ala151Glu	missense_variant	6/15	1	NM_006666.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Dec 01, 2022

The c.452C>A (p.A151E) alteration is located in exon 6 (coding exon 6) of the RUVBL2 gene. This alteration results from a C to A substitution at nucleotide position 452, causing the alanine (A) at amino acid position 151 to be replaced by a glutamic acid (E). 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Uncertain	0.51	D;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.097	B;.;.;.
Vest4		0.71
MutPred		0.48		Gain of disorder (P = 0.0138);.;.;.;
MVP		0.60
MPC		1.3
ClinPred		0.83	D
GERP RS		4.5
Varity_R		0.36
gMVP		0.87

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: chr19-49510615;