8-89924867-A-G

Variant summary

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

The NM_001126111.3(OSGIN2):c.985A>G(p.Met329Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: OSGIN2 NM_001126111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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=0.038650155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSGIN2	NM_001126111.3	c.985A>G	p.Met329Val	missense_variant	6/6	ENST00000451899.7
OSGIN2	NM_004337.2	c.853A>G	p.Met285Val	missense_variant	6/6
OSGIN2	XM_011517287.4	c.853A>G	p.Met285Val	missense_variant	6/6
OSGIN2	XM_011517288.4	c.454A>G	p.Met152Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSGIN2	ENST00000451899.7	c.985A>G	p.Met329Val	missense_variant	6/6	1	NM_001126111.3
OSGIN2	ENST00000297438.6	c.853A>G	p.Met285Val	missense_variant	6/6	1		P1
OSGIN2	ENST00000647849.1	c.853A>G	p.Met285Val	missense_variant	6/6			P1
NBN	ENST00000697292.1	c.*513T>C		3_prime_UTR_variant	17/17			P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152180 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251100 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

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

Aug 13, 2021

The c.985A>G (p.M329V) alteration is located in exon 6 (coding exon 6) of the OSGIN2 gene. This alteration results from a A to G substitution at nucleotide position 985, causing the methionine (M) at amino acid position 329 to be replaced by a valine (V). 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	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	9.8
Dann	Benign	0.90
DEOGEN2	Benign	0.033	T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.75	D;D
PrimateAI	Benign	0.30	T
Polyphen		0.0	B;B;B
Vest4		0.15, 0.15
MVP		0.27
MPC		0.35
ClinPred		0.019	T
GERP RS		1.8
Varity_R		0.057
gMVP		0.43

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: rs202111827; hg19: chr8-90937095; COSMIC: COSV52409327; COSMIC: COSV52409327;