8-89924710-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001126111.3(OSGIN2):c.828G>C(p.Lys276Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,998 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K276Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: OSGIN2 NM_001126111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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 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=0.1308167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSGIN2	NM_001126111.3	c.828G>C	p.Lys276Asn	missense_variant	6/6	ENST00000451899.7
OSGIN2	NM_004337.2	c.696G>C	p.Lys232Asn	missense_variant	6/6
OSGIN2	XM_011517287.4	c.696G>C	p.Lys232Asn	missense_variant	6/6
OSGIN2	XM_011517288.4	c.297G>C	p.Lys99Asn	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSGIN2	ENST00000451899.7	c.828G>C	p.Lys276Asn	missense_variant	6/6	1	NM_001126111.3
OSGIN2	ENST00000297438.6	c.696G>C	p.Lys232Asn	missense_variant	6/6	1		P1
OSGIN2	ENST00000647849.1	c.696G>C	p.Lys232Asn	missense_variant	6/6			P1
NBN	ENST00000697292.1	c.*670C>G		3_prime_UTR_variant	17/17			P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727202

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.00

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 23, 2021

The c.828G>C (p.K276N) alteration is located in exon 6 (coding exon 6) of the OSGIN2 gene. This alteration results from a G to C substitution at nucleotide position 828, causing the lysine (K) at amino acid position 276 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.046
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.41	T
Polyphen		0.015	B;B;B
Vest4		0.30, 0.33
MutPred		0.37		Loss of methylation at K232 (P = 0.0079);Loss of methylation at K232 (P = 0.0079);.;
MVP		0.36
MPC		0.41
ClinPred		0.58	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.44

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: rs368481675; hg19: chr8-90936938;