16-83965249-C-G

Position:

• chr16-83965249-C-G

Variant summary

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

The NM_182981.3(OSGIN1):​c.676C>G​(p.Leu226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OSGIN1 NM_182981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

Genes affected

OSGIN1 (HGNC:30093): (oxidative stress induced growth inhibitor 1) This gene encodes an oxidative stress response protein that regulates cell death. Expression of the gene is regulated by p53 and is induced by DNA damage. The protein regulates apoptosis by inducing cytochrome c release from mitochondria. It also appears to be a key regulator of both inflammatory and anti-inflammatory molecules. The loss of this protein correlates with uncontrolled cell growth and tumor formation. Naturally occurring read-through transcription exists between this gene and the neighboring upstream malonyl-CoA decarboxylase (MLYCD) gene, but the read-through transcripts are unlikely to produce a protein product. [provided by RefSeq, Aug 2011]

NECAB2 (HGNC:23746): (N-terminal EF-hand calcium binding protein 2) The protein encoded by this gene is a neuronal calcium-binding protein that binds to and modulates the function of at least two receptors, adenosine A(2A) receptor and metabotropic glutamate receptor type 5. [provided by RefSeq, Jul 2016]

OSGIN1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041880578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSGIN1	NM_182981.3	c.676C>G	p.Leu226Val	missense_variant	6/6	ENST00000393306.6	NP_892026.1
NECAB2	XM_047434240.1	c.-23+13C>G		intron_variant			XP_047290196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN1	ENST00000393306.6	c.676C>G	p.Leu226Val	missense_variant	6/6	1	NM_182981.3	ENSP00000376983.1
OSGIN1	ENST00000361711.7	c.676C>G	p.Leu226Val	missense_variant	6/6	2		ENSP00000355374.3
OSGIN1	ENST00000343939.6	n.1308C>G		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Mar 06, 2023

The c.676C>G (p.L226V) alteration is located in exon 6 (coding exon 5) of the OSGIN1 gene. This alteration results from a C to G substitution at nucleotide position 676, causing the leucine (L) at amino acid position 226 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.4
DANN	Benign	0.59
DEOGEN2	Benign	0.0026	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.26	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.64	.;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.23	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0060	.;B;.
Vest4		0.065
MutPred		0.30		.;Gain of glycosylation at S306 (P = 0.0773);.;
MVP		0.092
MPC		0.096
ClinPred		0.071	T
GERP RS		-0.23
Varity_R		0.037
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2084262721; hg19: chr16-83998854;