12-112997643-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002535.3(OAS2):c.751G>A(p.Val251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,613,988 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: OAS2 NM_002535.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11

Genes affected

OAS2 (HGNC:8087): (2'-5'-oligoadenylate synthetase 2) This gene encodes a member of the 2-5A synthetase family, essential proteins involved in the innate immune response to viral infection. The encoded protein is induced by interferons and uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2',5'-oligoadenylates (2-5As). These molecules activate latent RNase L, which results in viral RNA degradation and the inhibition of viral replication. The three known members of this gene family are located in a cluster on chromosome 12. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

(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=0.10391095).
• BP6: Variant 12-112997643-G-A is Benign according to our data. Variant chr12-112997643-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2522083.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OAS2	NM_002535.3	c.751G>A	p.Val251Ile	missense_variant	4/10	ENST00000392583.7
OAS2	NM_016817.3	c.751G>A	p.Val251Ile	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OAS2	ENST00000392583.7	c.751G>A	p.Val251Ile	missense_variant	4/10	1	NM_002535.3	P2
	ENST00000552784.1	n.353+19756C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000598 AC: 15 AN: 251044 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000999 AC: 146 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.0000963 AC XY: 70 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Jun 06, 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	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.1
Dann	Benign	0.89
DEOGEN2	Benign	0.085	T;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.42	N;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.099	T;T;D;.
Sift4G	Benign	0.17	T;T;D;T
Polyphen		0.10	B;B;.;.
Vest4		0.11
MutPred		0.63		Gain of catalytic residue at L252 (P = 0.0524);Gain of catalytic residue at L252 (P = 0.0524);.;Gain of catalytic residue at L252 (P = 0.0524);
MVP		0.42
MPC		0.18
ClinPred		0.042	T
GERP RS		3.2
Varity_R		0.037
gMVP		0.12

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: rs768169767; hg19: chr12-113435448; COSMIC: COSV60804667; COSMIC: COSV60804667;