rs147605088

chr12-56354489-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005419.4(STAT2):c.759C>T(p.His253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,614,188 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (9 hom.)
• Consequence: STAT2 NM_005419.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.23

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-56354489-G-A is Benign according to our data. Variant chr12-56354489-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 403494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56354489-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00164 (250/152310) while in subpopulation AMR AF= 0.0036 (55/15298). AF 95% confidence interval is 0.00284. There are 1 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT2	NM_005419.4	c.759C>T	p.His253=	synonymous_variant	8/24	ENST00000314128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT2	ENST00000314128.9	c.759C>T	p.His253=	synonymous_variant	8/24	1	NM_005419.4	P2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152192 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00209 AC: 526 AN: 251462 Hom.: 4 AF XY: 0.00211 AC XY: 287 AN XY: 135906

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00231 AC: 3373 AN: 1461878 Hom.: 9 Cov.: 32 AF XY: 0.00230 AC XY: 1670 AN XY: 727240

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00402

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152310 Hom.: 1 Cov.: 31 AF XY: 0.00145 AC XY: 108 AN XY: 74472

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00237

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	STAT2: BP4, BP7, BS2 -

not specified Benign:1

Likely 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: LOF variant in this gene associated with decreased antiviral immunity. Not enough evidence for this variant to go above VUS. -

Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

STAT2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.4
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs147605088; hg19: chr12-56748273; COSMIC: COSV58475353; COSMIC: COSV58475353;