rs61754170

chr12-56343472-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

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. 14/19 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.530

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, STAT2
• 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_single_submitter, 1 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT2	NM_005419.4	c.2473G>T	p.Gly825Cys	missense_variant	24/24	ENST00000314128.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2270 AN: 152154 Hom.: 32 Cov.: 32

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.: 63 AF XY: 0.0168 AC XY: 2286 AN XY: 135878

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.: 31 AF XY: 0.0188 AC XY: 13646 AN XY: 727212

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.: 32 Cov.: 32 AF XY: 0.0161 AC XY: 1198 AN XY: 74470

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.: 19

Bravo AF: 0.0109

ExAC AF: 0.0175 AC: 2120

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
Dann	Benign	0.77
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs61754170; hg19: chr12-56737256; COSMIC: COSV57336150; COSMIC: COSV57336150;