19-49007317-C-G

Variant names:

• chr19-49007317-C-G
• NM_006666.3:c.411C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006666.3(RUVBL2):​c.411C>G​(p.Ile137Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUVBL2 NM_006666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3	c.411C>G	p.Ile137Met	missense_variant	Exon 6 of 15	ENST00000595090.6	NP_006657.1
RUVBL2	NM_001321190.2	c.309C>G	p.Ile103Met	missense_variant	Exon 6 of 15		NP_001308119.1
RUVBL2	NM_001321191.1	c.276C>G	p.Ile92Met	missense_variant	Exon 6 of 15		NP_001308120.1
RUVBL2	NR_135578.2	n.436C>G		non_coding_transcript_exon_variant	Exon 6 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUVBL2	ENST00000595090.6	c.411C>G	p.Ile137Met	missense_variant	Exon 6 of 15	1	NM_006666.3	ENSP00000473172.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411C>G (p.I137M) alteration is located in exon 6 (coding exon 6) of the RUVBL2 gene. This alteration results from a C to G substitution at nucleotide position 411, causing the isoleucine (I) at amino acid position 137 to be replaced by a methionine (M). 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	0.30
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T;T;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	2.0	M;.;.;.
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.024	D;D;T;D
Polyphen		0.049	B;.;.;.
Vest4		0.74
MutPred		0.69		Gain of sheet (P = 0.0149);.;.;.;
MVP		0.40
MPC		1.2
ClinPred		0.69	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr19-49510574;