12-56343467-C-A

Position:

chr12-56343467-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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.339

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=0.004781902).

BP6

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

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

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT2	NM_005419.4 linkuse as main transcript	c.2478G>T	p.Gln826His	missense_variant	24/24	ENST00000314128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT2	ENST00000314128.9 linkuse as main transcript	c.2478G>T	p.Gln826His	missense_variant	24/24	1	NM_005419.4	P2	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

GnomAD3 exomes

AF:

0.00789

AC:

1985

AN:

251442

Hom.:

AF XY:

0.00790

AC XY:

1073

AN XY:

135886

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 SAS exome

AF:

0.00163

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

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00528

Gnomad4 ASJ exome

AF:

0.0345

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00208

Gnomad4 FIN exome

AF:

0.00790

Gnomad4 NFE exome

AF:

0.00957

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.00788

AC:

1200

AN:

152292

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00798

Gnomad4 ASJ

AF:

0.0378

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00706

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.0116

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/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	STAT2: BP4, BS2 -

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 29, 2024

- -

STAT2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2019

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

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;.

MutationTaster

Benign

1.0

N;N

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

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

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