12-56343473-A-G

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.2472T>C(p.Ala824=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,614,186 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., cov: 32)
  • Exomes 𝑓: 0.019 (334 hom.)
• Consequence: STAT2 NM_005419.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0190

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=-0.89).
• BP6: Variant 12-56343473-A-G is Benign according to our data. Variant chr12-56343473-A-G is described in ClinVar as [Benign]. Clinvar id is 403492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0149 (2272/152336) while in subpopulation NFE AF= 0.0208 (1417/68020). AF 95% confidence interval is 0.0199. There are 32 homozygotes in gnomad4. There are 1199 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.2472T>C	p.Ala824=	synonymous_variant	24/24	ENST00000314128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT2	ENST00000314128.9	c.2472T>C	p.Ala824=	synonymous_variant	24/24	1	NM_005419.4	P2

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2271 AN: 152218 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: 0.000576

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: 251412 Hom.: 62 AF XY: 0.0168 AC XY: 2287 AN XY: 135868

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: 0.0181

Gnomad FIN exome AF: 0.0422

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0187 AC: 27399 AN: 1461850 Hom.: 334 Cov.: 31 AF XY: 0.0188 AC XY: 13657 AN XY: 727216

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: 2272 AN: 152336 Hom.: 32 Cov.: 32 AF XY: 0.0161 AC XY: 1199 AN XY: 74498

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: 0.0178 Hom.: 19

Bravo AF: 0.0109

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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.2473G>T variant (per exac) -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.8
Dann	Benign	0.40

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: rs61754171; hg19: chr12-56737257; COSMIC: COSV57336152; COSMIC: COSV57336152;