12-56343472-C-A

Position:

chr12-56343472-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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 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=0.0025007725).

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT2	NM_005419.4 linkuse as main transcript	c.2473G>T	p.Gly825Cys	missense_variant	24/24	ENST00000314128.9	NP_005410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT2	ENST00000314128.9 linkuse as main transcript	c.2473G>T	p.Gly825Cys	missense_variant	24/24	1	NM_005419.4	ENSP00000315768	P2	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

GnomAD3 exomes

AF:

0.0162

AC:

4082

AN:

251428

Hom.:

AF XY:

0.0168

AC XY:

2286

AN XY:

135878

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 SAS exome

AF:

0.0180

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

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00662

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0194

Gnomad4 FIN exome

AF:

0.0407

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0166

GnomAD4 genome

AF:

0.0149

AC:

2271

AN:

152272

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1198

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.0466

Gnomad4 NFE

AF:

0.0208

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0176

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

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

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

0.086

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

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;.

MutationTaster

Benign

1.0

N;N

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

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.

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