8-89924652-T-C

Position:

• chr8-89924652-T-C

Variant summary

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

The NM_001126111.3(OSGIN2):​c.770T>C​(p.Ile257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,002 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: OSGIN2 NM_001126111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.853

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=0.04662597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSGIN2	NM_001126111.3	c.770T>C	p.Ile257Thr	missense_variant	6/6	ENST00000451899.7	NP_001119583.1
OSGIN2	NM_004337.2	c.638T>C	p.Ile213Thr	missense_variant	6/6		NP_004328.1
OSGIN2	XM_011517287.4	c.638T>C	p.Ile213Thr	missense_variant	6/6		XP_011515589.1
OSGIN2	XM_011517288.4	c.239T>C	p.Ile80Thr	missense_variant	3/3		XP_011515590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN2	ENST00000451899.7	c.770T>C	p.Ile257Thr	missense_variant	6/6	1	NM_001126111.3	ENSP00000396445.2
OSGIN2	ENST00000297438.6	c.638T>C	p.Ile213Thr	missense_variant	6/6	1		ENSP00000297438.2
OSGIN2	ENST00000647849.1	c.638T>C	p.Ile213Thr	missense_variant	6/6			ENSP00000497119.1
NBN	ENST00000697292	c.*728A>G		3_prime_UTR_variant	17/17			ENSP00000513229.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.00000398 AC: 1 AN: 251004 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135642

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727206

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

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 25, 2024

The c.770T>C (p.I257T) alteration is located in exon 6 (coding exon 6) of the OSGIN2 gene. This alteration results from a T to C substitution at nucleotide position 770, causing the isoleucine (I) at amino acid position 257 to be replaced by a threonine (T). 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	0.059
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.7
DANN	Benign	0.73
DEOGEN2	Benign	0.014	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.24	.;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N;N;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.1	.;N;N
REVEL	Benign	0.014
Sift	Benign	0.58	.;T;T
Sift4G	Benign	0.58	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.041, 0.038
MutPred		0.29		Gain of phosphorylation at I213 (P = 0.0172);Gain of phosphorylation at I213 (P = 0.0172);.;
MVP		0.068
MPC		0.44
ClinPred		0.027	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.34

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: rs903445053; hg19: chr8-90936880;