NM_005419.4:c.2473G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005419.4(STAT2):c.2473G>T(p.Gly825Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,614,114 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G825D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 32 hom., cov: 32)

Exomes 𝑓: 0.019 ( 334 hom. )

Consequence

STAT2
NM_005419.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.530

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:

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=0.0025007725).

BP6

Variant 12-56343472-C-A is Benign according to our data. Variant chr12-56343472-C-A is described in ClinVar as [Benign]. Clinvar id is 403491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56343472-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0149 (2271/152272) while in subpopulation NFE AF = 0.0208 (1416/68012). AF 95% confidence interval is 0.0199. There are 32 homozygotes in GnomAd4. There are 1198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT2	NM_005419.4 link	c.2473G>T	p.Gly825Cys	missense_variant	Exon 24 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.2473G>T	p.Gly825Cys	missense_variant	Exon 24 of 24	1	NM_005419.4	ENSP00000315768.4		P52630-3

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2270

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.0466

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0208

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0162

AC:

4082

AN:

251428

AF XY:

0.0168

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.00714

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.0187

AC:

27379

AN:

1461842

Hom.:

334

Cov.:

AF XY:

0.0188

AC XY:

13646

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33478

American (AMR)

AF:

0.00284

AC:

127

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

173

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0194

AC:

1674

AN:

86252

European-Finnish (FIN)

AF:

0.0407

AC:

2176

AN:

53414

Middle Eastern (MID)

AF:

0.00972

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0199

AC:

22099

AN:

1111980

Other (OTH)

AF:

0.0166

AC:

1001

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1470

2940

4411

5881

7351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0149

AC:

2271

AN:

152272

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1198

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41540

American (AMR)

AF:

0.00536

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.0178

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0466

AC:

495

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0208

AC:

1416

AN:

68012

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0144

Hom.:

Bravo

AF:

0.0109

ExAC

AF:

0.0175

AC:

2120

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

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: In cis with c.2472T>C variant (per exac) -

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

0.086

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.090

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.013

Sift

Benign

0.10

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0080

B;.

Vest4

0.058

MPC

0.45

ClinPred

0.0038

GERP RS

0.50

Varity_R

0.14

gMVP

0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

NM_005419.4:c.2473G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over