rs147605088

Variant names:

• chr12-56354489-G-A
• rs147605088
• NM_005419.4:c.759C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005419.4(STAT2):​c.759C>T​(p.His253His) 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:7
• Conservation: PhyloP100: -1.23
• Publications: 4 publications found

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: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• pseudo-TORCH syndrome 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 403494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT2	NM_005419.4	MANE Select	c.759C>T	p.His253His	synonymous	Exon 8 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.747C>T	p.His249His	synonymous	Exon 8 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.759C>T	p.His253His	synonymous	Exon 8 of 23	NP_001372043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT2	ENST00000314128.9	TSL:1 MANE Select	c.759C>T	p.His253His	synonymous	Exon 8 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000922389.1		c.759C>T	p.His253His	synonymous	Exon 8 of 24	ENSP00000592448.1
	STAT2	ENST00000960656.1		c.756C>T	p.His252His	synonymous	Exon 8 of 24	ENSP00000630715.1

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

GnomAD2 exomes AF: 0.00209 AC: 526 AN: 251462 AF XY: 0.00211

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 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

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00402 AC: 180 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00133 AC: 115 AN: 86256

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53418

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00252 AC: 2799 AN: 1112012

Other (OTH) AF: 0.00270 AC: 163 AN: 60394

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

African (AFR) AF: 0.000553 AC: 23 AN: 41578

American (AMR) AF: 0.00360 AC: 55 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (1)
-	-	1	STAT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.73
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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