6-42592200-G-A

Variant names:

• chr6-42592200-G-A
• rs1402787631
• NM_001363705.2:c.388G>A

Variant summary

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

The NM_001363705.2(UBR2):​c.388G>A​(p.Gly130Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,700 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UBR2 NM_001363705.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.92

Genes affected

UBR2 (HGNC:21289): (ubiquitin protein ligase E3 component n-recognin 2) Enables leucine binding activity. Involved in cellular response to leucine and negative regulation of TOR signaling. Predicted to be located in cytosol. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm. Predicted to colocalize with chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2900958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBR2	NM_001363705.2	c.388G>A	p.Gly130Arg	missense_variant	Exon 3 of 47	ENST00000372901.2	NP_001350634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBR2	ENST00000372901.2	c.388G>A	p.Gly130Arg	missense_variant	Exon 3 of 47	5	NM_001363705.2	ENSP00000361992.1
UBR2	ENST00000372899.6	c.388G>A	p.Gly130Arg	missense_variant	Exon 3 of 47	1		ENSP00000361990.1
UBR2	ENST00000372903.6	c.388G>A	p.Gly130Arg	missense_variant	Exon 3 of 12	1		ENSP00000361994.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445700 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719372

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388G>A (p.G130R) alteration is located in exon 3 (coding exon 3) of the UBR2 gene. This alteration results from a G to A substitution at nucleotide position 388, causing the glycine (G) at amino acid position 130 to be replaced by an arginine (R). 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	0.31
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.56	N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.31	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.47	T;D;D
Sift4G	Benign	0.079	T;T;T
Polyphen		0.059	B;B;.
Vest4		0.54
MutPred		0.48		Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);
MVP		0.23
MPC		0.51
ClinPred		0.83	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs1402787631; hg19: chr6-42559938;