rs2066807

Positions:

chr12-56346898-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005419.4(STAT2):c.1782G>C(p.Met594Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,614,160 control chromosomes in the GnomAD database, including 3,148 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 226 hom., cov: 31)

Exomes 𝑓: 0.060 ( 2922 hom. )

Consequence

STAT2
NM_005419.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.51

Variant links:

Genes affected

STAT2 (HGNC:11363): (signal transducer and activator of transcription 2) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. In response to interferon (IFN), this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. The protein mediates innate antiviral activity. Mutations in this gene result in Immunodeficiency 44. [provided by RefSeq, Aug 2020]

STAT2 links:

STAT2 (HGNC:):

STAT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT2. . Gene score misZ 2.5952 (greater than the threshold 3.09). Trascript score misZ 3.6431 (greater than threshold 3.09). GenCC has associacion of gene with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, pseudo-TORCH syndrome 3.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018221736).

BP6

Variant 12-56346898-C-G is Benign according to our data. Variant chr12-56346898-C-G is described in ClinVar as [Benign]. Clinvar id is 403493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56346898-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT2	NM_005419.4 linkuse as main transcript	c.1782G>C	p.Met594Ile	missense_variant	20/24	ENST00000314128.9	NP_005410.1	P52630-3R9QE65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT2	ENST00000314128.9 linkuse as main transcript	c.1782G>C	p.Met594Ile	missense_variant	20/24	1	NM_005419.4	ENSP00000315768.4		P52630-3

Frequencies

GnomAD3 genomes

AF:

0.0458

AC:

6973

AN:

152168

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0543

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.0343

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.0537

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0684

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0490

AC:

12319

AN:

251374

Hom.:

370

AF XY:

0.0485

AC XY:

6592

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00929

Gnomad AMR exome

AF:

0.0541

Gnomad ASJ exome

AF:

0.0238

Gnomad EAS exome

AF:

0.0286

Gnomad SAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.0557

Gnomad NFE exome

AF:

0.0644

Gnomad OTH exome

AF:

0.0450

GnomAD4 exome

AF:

0.0595

AC:

86991

AN:

1461874

Hom.:

2922

Cov.:

AF XY:

0.0590

AC XY:

42923

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00941

Gnomad4 AMR exome

AF:

0.0536

Gnomad4 ASJ exome

AF:

0.0244

Gnomad4 EAS exome

AF:

0.0360

Gnomad4 SAS exome

AF:

0.0223

Gnomad4 FIN exome

AF:

0.0546

Gnomad4 NFE exome

AF:

0.0665

Gnomad4 OTH exome

AF:

0.0546

GnomAD4 genome

AF:

0.0459

AC:

6992

AN:

152286

Hom.:

226

Cov.:

AF XY:

0.0450

AC XY:

3354

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.0543

Gnomad4 ASJ

AF:

0.0208

Gnomad4 EAS

AF:

0.0342

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.0537

Gnomad4 NFE

AF:

0.0685

Gnomad4 OTH

AF:

0.0350

Alfa

AF:

0.0630

Hom.:

278

Bravo

AF:

0.0424

TwinsUK

AF:

0.0672

AC:

249

ALSPAC

AF:

0.0625

AC:

241

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0627

AC:

539

ExAC

AF:

0.0481

AC:

5837

Asia WGS

AF:

0.0750

AC:

259

AN:

3478

EpiCase

AF:

0.0619

EpiControl

AF:

0.0578

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.42

DANN

Benign

0.61

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.024

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

-0.95

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.54

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.22

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0

B;.

Vest4

0.012

MutPred

0.23

Loss of disorder (P = 0.0713);.;

MPC

0.44

ClinPred

0.0038

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.044

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over