8-89924701-C-A

Position:

• chr8-89924701-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001126111.3(OSGIN2):​c.819C>A​(p.Asn273Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,744 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: OSGIN2 NM_001126111.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.314

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024796367).
• BP6: Variant 8-89924701-C-A is Benign according to our data. Variant chr8-89924701-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2465878.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSGIN2	NM_001126111.3	c.819C>A	p.Asn273Lys	missense_variant	6/6	ENST00000451899.7	NP_001119583.1
OSGIN2	NM_004337.2	c.687C>A	p.Asn229Lys	missense_variant	6/6		NP_004328.1
OSGIN2	XM_011517287.4	c.687C>A	p.Asn229Lys	missense_variant	6/6		XP_011515589.1
OSGIN2	XM_011517288.4	c.288C>A	p.Asn96Lys	missense_variant	3/3		XP_011515590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN2	ENST00000451899.7	c.819C>A	p.Asn273Lys	missense_variant	6/6	1	NM_001126111.3	ENSP00000396445
OSGIN2	ENST00000297438.6	c.687C>A	p.Asn229Lys	missense_variant	6/6	1		ENSP00000297438	P1
OSGIN2	ENST00000647849.1	c.687C>A	p.Asn229Lys	missense_variant	6/6			ENSP00000497119	P1
NBN	ENST00000697292.1	c.*679G>T		3_prime_UTR_variant	17/17			ENSP00000513229	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250840 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135548

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727164

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.1
DANN	Benign	0.69
DEOGEN2	Benign	0.021	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.54	.;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.72	.;N;N
REVEL	Benign	0.056
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.92	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.049, 0.025
MutPred		0.36		Gain of methylation at N229 (P = 0.0038);Gain of methylation at N229 (P = 0.0038);.;
MVP		0.22
MPC		0.40
ClinPred		0.028	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.16

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: rs746142507; hg19: chr8-90936929;