8-89924708-A-C

Position:

• chr8-89924708-A-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.826A>C​(p.Lys276Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,776 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OSGIN2 NM_001126111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

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=0.21555042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSGIN2	NM_001126111.3	c.826A>C	p.Lys276Gln	missense_variant	6/6	ENST00000451899.7	NP_001119583.1
OSGIN2	NM_004337.2	c.694A>C	p.Lys232Gln	missense_variant	6/6		NP_004328.1
OSGIN2	XM_011517287.4	c.694A>C	p.Lys232Gln	missense_variant	6/6		XP_011515589.1
OSGIN2	XM_011517288.4	c.295A>C	p.Lys99Gln	missense_variant	3/3		XP_011515590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN2	ENST00000451899.7	c.826A>C	p.Lys276Gln	missense_variant	6/6	1	NM_001126111.3	ENSP00000396445
OSGIN2	ENST00000297438.6	c.694A>C	p.Lys232Gln	missense_variant	6/6	1		ENSP00000297438	P1
OSGIN2	ENST00000647849.1	c.694A>C	p.Lys232Gln	missense_variant	6/6			ENSP00000497119	P1
NBN	ENST00000697292.1	c.*672T>G		3_prime_UTR_variant	17/17			ENSP00000513229	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727196

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: 0.00

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

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

Jan 26, 2023

The c.826A>C (p.K276Q) alteration is located in exon 6 (coding exon 6) of the OSGIN2 gene. This alteration results from a A to C substitution at nucleotide position 826, causing the lysine (K) at amino acid position 276 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.68	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.44	.;N;N
REVEL	Benign	0.15
Sift	Benign	0.29	.;T;T
Sift4G	Benign	0.36	.;T;T
Polyphen		0.91	P;P;D
Vest4		0.14, 0.14
MutPred		0.37		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);.;
MVP		0.54
MPC		0.39
ClinPred		0.54	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.35

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: rs1809279031; hg19: chr8-90936936;