12-56343467-C-A

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.2478G>T(p.Gln826His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,614,160 control chromosomes in the GnomAD database, including 87 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 77 hom. )

Consequence

STAT2
NM_005419.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.339

Publications

22 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=0.004781902).

BP6

Variant 12-56343467-C-A is Benign according to our data. Variant chr12-56343467-C-A is described in ClinVar as [Benign]. Clinvar id is 475692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00788 (1200/152292) while in subpopulation NFE AF = 0.0114 (774/68022). AF 95% confidence interval is 0.0107. There are 10 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT2	NM_005419.4 link	c.2478G>T	p.Gln826His	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.2478G>T	p.Gln826His	missense_variant	Exon 24 of 24	1	NM_005419.4	ENSP00000315768.4		P52630-3

Frequencies

GnomAD3 genomes

AF:

0.00789

AC:

1201

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00789

AC:

1985

AN:

251442

AF XY:

0.00790

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.00902

AC:

13184

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00906

AC XY:

6588

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33480

American (AMR)

AF:

0.00528

AC:

236

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0345

AC:

901

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00208

AC:

179

AN:

86258

European-Finnish (FIN)

AF:

0.00790

AC:

422

AN:

53420

Middle Eastern (MID)

AF:

0.0210

AC:

121

AN:

5764

European-Non Finnish (NFE)

AF:

0.00957

AC:

10646

AN:

1111998

Other (OTH)

AF:

0.0104

AC:

630

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

714

1428

2142

2856

3570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00788

AC:

1200

AN:

152292

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41556

American (AMR)

AF:

0.00798

AC:

122

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0378

AC:

131

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00706

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

774

AN:

68022

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

131

197

262

328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00721

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0128

AC:

110

ExAC

AF:

0.00769

AC:

934

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0138

EpiControl

AF:

0.0128

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

STAT2: PP2, BP4, BS1, BS2 -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

STAT2-related disorder

Benign:1

Apr 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.66

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

L;.

PhyloP100

0.34

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.082

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.0060

B;.

Vest4

0.14

MutPred

0.14

Gain of catalytic residue at N827 (P = 0.051);.;

MVP

0.35

MPC

0.40

ClinPred

0.0072

GERP RS

3.5

Varity_R

0.14

gMVP

0.24

Mutation Taster

=93/7

polymorphism

(source)

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

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12-56343467-C-A

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