rs2066807

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M594V) has been classified as Uncertain significance.

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

Publications

107 publications found

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 Gene-Disease associations (from GenCC):

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
pseudo-TORCH syndrome 3
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

STAT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 403493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
STAT2	NM_005419.4 link	c.1782G>C	p.Met594Ile	missense_variant	Exon 20 of 24	ENST00000314128.9	NP_005410.1	P52630-3R9QE65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT2	ENST00000314128.9 link	c.1782G>C	p.Met594Ile	missense_variant	Exon 20 of 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

GnomAD2 exomes

AF:

0.0490

AC:

12319

AN:

251374

AF XY:

0.0485

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 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

African (AFR)

AF:

0.00941

AC:

315

AN:

33478

American (AMR)

AF:

0.0536

AC:

2396

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

637

AN:

26136

East Asian (EAS)

AF:

0.0360

AC:

1428

AN:

39700

South Asian (SAS)

AF:

0.0223

AC:

1927

AN:

86258

European-Finnish (FIN)

AF:

0.0546

AC:

2917

AN:

53416

Middle Eastern (MID)

AF:

0.0234

AC:

135

AN:

5768

European-Non Finnish (NFE)

AF:

0.0665

AC:

73936

AN:

1111998

Other (OTH)

AF:

0.0546

AC:

3300

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

5090

10180

15269

20359

25449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2682

5364

8046

10728

13410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0459

AC:

6992

AN:

152286

Hom.:

226

Cov.:

AF XY:

0.0450

AC XY:

3354

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0111

AC:

461

AN:

41560

American (AMR)

AF:

0.0543

AC:

830

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

AN:

3468

East Asian (EAS)

AF:

0.0342

AC:

177

AN:

5178

South Asian (SAS)

AF:

0.0199

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0537

AC:

570

AN:

10606

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0685

AC:

4657

AN:

68028

Other (OTH)

AF:

0.0350

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

338

677

1015

1354

1692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.

PhyloP100

-2.5

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over