8-89924739-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001126111.3(OSGIN2):c.857G>A(p.Arg286Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: OSGIN2 NM_001126111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

OSGIN2 (HGNC:1355): (oxidative stress induced growth inhibitor family member 2) Predicted to enable growth factor activity. Predicted to be involved in negative regulation of cell growth. [provided by Alliance of Genome Resources, Apr 2022]

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022833437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSGIN2	NM_001126111.3	c.857G>A	p.Arg286Gln	missense_variant	6/6	ENST00000451899.7
OSGIN2	NM_004337.2	c.725G>A	p.Arg242Gln	missense_variant	6/6
OSGIN2	XM_011517287.4	c.725G>A	p.Arg242Gln	missense_variant	6/6
OSGIN2	XM_011517288.4	c.326G>A	p.Arg109Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSGIN2	ENST00000451899.7	c.857G>A	p.Arg286Gln	missense_variant	6/6	1	NM_001126111.3
OSGIN2	ENST00000297438.6	c.725G>A	p.Arg242Gln	missense_variant	6/6	1		P1
OSGIN2	ENST00000647849.1	c.725G>A	p.Arg242Gln	missense_variant	6/6			P1
NBN	ENST00000697292.1	c.*641C>T		3_prime_UTR_variant	17/17			P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000598 AC: 15 AN: 250752 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000576 AC: 7

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

Nov 17, 2023

The c.857G>A (p.R286Q) alteration is located in exon 6 (coding exon 6) of the OSGIN2 gene. This alteration results from a G to A substitution at nucleotide position 857, causing the arginine (R) at amino acid position 286 to be replaced by a glutamine (Q). 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	0.073
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.044	T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.97	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.28	T
Polyphen		0.0010	B;B;B
Vest4		0.088, 0.085
MutPred		0.50		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;
MVP		0.30
MPC		0.40
ClinPred		0.074	T
GERP RS		3.5
Varity_R		0.051
gMVP		0.31

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: rs551259875; hg19: chr8-90936967;