8-89925243-T-C

Position:

chr8-89925243-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001126111.3(OSGIN2):c.1361T>C(p.Val454Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

OSGIN2
NM_001126111.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Variant links:

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]

OSGIN2 links:

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]

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12940893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OSGIN2	NM_001126111.3 linkuse as main transcript	c.1361T>C	p.Val454Ala	missense_variant	6/6	ENST00000451899.7	NP_001119583.1
OSGIN2	NM_004337.2 linkuse as main transcript	c.1229T>C	p.Val410Ala	missense_variant	6/6		NP_004328.1
OSGIN2	XM_011517287.4 linkuse as main transcript	c.1229T>C	p.Val410Ala	missense_variant	6/6		XP_011515589.1
OSGIN2	XM_011517288.4 linkuse as main transcript	c.830T>C	p.Val277Ala	missense_variant	3/3		XP_011515590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN2	ENST00000451899.7 linkuse as main transcript	c.1361T>C	p.Val454Ala	missense_variant	6/6	1	NM_001126111.3	ENSP00000396445		Q9Y236-2
OSGIN2	ENST00000297438.6 linkuse as main transcript	c.1229T>C	p.Val410Ala	missense_variant	6/6	1		ENSP00000297438	P1	Q9Y236-1
OSGIN2	ENST00000647849.1 linkuse as main transcript	c.1229T>C	p.Val410Ala	missense_variant	6/6			ENSP00000497119	P1	Q9Y236-1
NBN	ENST00000697292.1 linkuse as main transcript	c.*137A>G		3_prime_UTR_variant	17/17			ENSP00000513229	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251088

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.1361T>C (p.V454A) 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 1361, causing the valine (V) at amino acid position 454 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.038

T;T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.73

.;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.19

N;N;.

MutationTaster

Benign

0.60

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

.;N;N

REVEL

Benign

0.050

Sift

Benign

0.23

.;T;T

Sift4G

Benign

0.45

.;T;T

Polyphen

0.0020

B;B;B

Vest4

0.23, 0.23

MutPred

0.52

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;

MVP

0.068

MPC

0.42

ClinPred

0.083

GERP RS

3.5

Varity_R

0.050

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over