chr8-89924544-G-A

Variant summary

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

The NM_001126111.3(OSGIN2):​c.662G>A​(p.Arg221His) variant causes a missense change. The variant allele was found at a frequency of 0.0000595 in 1,612,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.000062 ( 0 hom. )

Consequence

OSGIN2
NM_001126111.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.09
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]
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]

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=0.165725).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OSGIN2NM_001126111.3 linkuse as main transcriptc.662G>A p.Arg221His missense_variant 6/6 ENST00000451899.7 NP_001119583.1
OSGIN2NM_004337.2 linkuse as main transcriptc.530G>A p.Arg177His missense_variant 6/6 NP_004328.1
OSGIN2XM_011517287.4 linkuse as main transcriptc.530G>A p.Arg177His missense_variant 6/6 XP_011515589.1
OSGIN2XM_011517288.4 linkuse as main transcriptc.131G>A p.Arg44His missense_variant 3/3 XP_011515590.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OSGIN2ENST00000451899.7 linkuse as main transcriptc.662G>A p.Arg221His missense_variant 6/61 NM_001126111.3 ENSP00000396445 Q9Y236-2
OSGIN2ENST00000297438.6 linkuse as main transcriptc.530G>A p.Arg177His missense_variant 6/61 ENSP00000297438 P1Q9Y236-1
OSGIN2ENST00000647849.1 linkuse as main transcriptc.530G>A p.Arg177His missense_variant 6/6 ENSP00000497119 P1Q9Y236-1
NBNENST00000697292.1 linkuse as main transcriptc.*836C>T 3_prime_UTR_variant 17/17 ENSP00000513229 P1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152016
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000562
AC:
14
AN:
248966
Hom.:
0
AF XY:
0.0000668
AC XY:
9
AN XY:
134806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000878
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000165
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000532
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000623
AC:
91
AN:
1460302
Hom.:
0
Cov.:
31
AF XY:
0.0000606
AC XY:
44
AN XY:
726408
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.000135
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000666
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152016
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74238
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000642
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000546
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsJan 08, 2024The c.662G>A (p.R221H) 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 662, causing the arginine (R) at amino acid position 221 to be replaced by a histidine (H). 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
0.067
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.014
T;T;.
Eigen
Benign
-0.22
Eigen_PC
Benign
0.034
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.87
.;D;D
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
N;N;.
MutationTaster
Benign
0.52
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.66
.;N;N
REVEL
Benign
0.050
Sift
Benign
0.48
.;T;T
Sift4G
Benign
0.20
.;T;T
Polyphen
0.047
B;B;B
Vest4
0.061, 0.068
MutPred
0.42
Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;
MVP
0.16
MPC
0.43
ClinPred
0.057
T
GERP RS
5.2
Varity_R
0.18
gMVP
0.40

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.

Other links and lift over

dbSNP: rs749844272; hg19: chr8-90936772; COSMIC: COSV52407540; COSMIC: COSV52407540; API