rs2066815

Variant names:

• chr12-56349260-G-A
• rs2066815
• NM_005419.4:c.1343C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_005419.4(STAT2):​c.1343C>T​(p.Thr448Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,614,200 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T448T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (47 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (319 hom.)
• Consequence: STAT2 NM_005419.4 missense, splice_region
• Scores: Splicing: ADA: 0.9775
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.40
• Publications: 12 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 12-56349260-G-A is Benign according to our data. Variant chr12-56349260-G-A is described in ClinVar as Benign. ClinVar VariationId is 475688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

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.1343C>T	p.Thr448Met	missense splice_region	Exon 16 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.1331C>T	p.Thr444Met	missense splice_region	Exon 16 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.1322C>T	p.Thr441Met	missense splice_region	Exon 15 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.1343C>T	p.Thr448Met	missense splice_region	Exon 16 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.273C>T		splice_region non_coding_transcript_exon	Exon 3 of 11
	STAT2	ENST00000922389.1		c.1343C>T	p.Thr448Met	missense splice_region	Exon 16 of 24	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.00700 AC: 1065 AN: 152192 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0167 AC: 4198 AN: 251438 AF XY: 0.0123

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00892

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.00386 AC: 5642 AN: 1461890 Hom.: 319 Cov.: 32 AF XY: 0.00322 AC XY: 2345 AN XY: 727246

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.106 AC: 4734 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00730 AC: 290 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000260 AC: 289 AN: 1112010

Other (OTH) AF: 0.00455 AC: 275 AN: 60396

GnomAD4 genome AF: 0.00706 AC: 1075 AN: 152310 Hom.: 47 Cov.: 31 AF XY: 0.00693 AC XY: 516 AN XY: 74462

African (AFR) AF: 0.00135 AC: 56 AN: 41572

American (AMR) AF: 0.0608 AC: 931 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00848 AC: 44 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00433 Hom.: 124

Bravo AF: 0.0131

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0126 AC: 1533

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0037	T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.58
MPC		1.2
ClinPred		0.040	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.84
Mutation Taster		=51/49	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.86
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: rs2066815; hg19: chr12-56743044;