dbSNP rs61754170: STAT2:p.Gly825Cys (chr12-56343472-C-A) – ACMG Classification: Benign (-20 pts)

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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. 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

Publications

11 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), G2P, Orphanet
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=0.0025007725).

BP6

Variant 12-56343472-C-A is Benign according to our data. Variant chr12-56343472-C-A is described in ClinVar as Benign. ClinVar VariationId is 403491.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 = 0.0149 (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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005419.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAT2	NM_005419.4	MANE Select	c.2473G>T	p.Gly825Cys	missense	Exon 24 of 24	NP_005410.1	P52630-3
STAT2	NM_198332.2		c.2461G>T	p.Gly821Cys	missense	Exon 24 of 24	NP_938146.1	P52630-4
STAT2	NM_001385114.1		c.2452G>T	p.Gly818Cys	missense	Exon 23 of 23	NP_001372043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAT2	ENST00000314128.9	TSL:1 MANE Select	c.2473G>T	p.Gly825Cys	missense	Exon 24 of 24	ENSP00000315768.4	P52630-3
STAT2	ENST00000556539.5	TSL:1	n.1403G>T		non_coding_transcript_exon	Exon 11 of 11
STAT2	ENST00000922389.1		c.2497G>T	p.Gly833Cys	missense	Exon 24 of 24	ENSP00000592448.1

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.0149

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0144

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.53

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

REVEL

Benign

0.013

Sift

Benign

0.10

Sift4G

Benign

0.13

Polyphen

0.0080

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over