12-56344189-A-G

Variant names:

• chr12-56344189-A-G
• rs2066808
• NM_005419.4:c.2103-54T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005419.4(STAT2):​c.2103-54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0877 in 1,510,784 control chromosomes in the GnomAD database, including 13,976 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (6199 hom., cov: 32)
  • Exomes 𝑓: 0.076 (7777 hom.)
• Consequence: STAT2 NM_005419.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 100 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.523 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.2103-54T>C		intron	N/A	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.2091-54T>C		intron	N/A	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.2082-54T>C		intron	N/A	NP_001372043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT2	ENST00000314128.9	TSL:1 MANE Select	c.2103-54T>C		intron	N/A	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.1033-54T>C		intron	N/A
	STAT2	ENST00000922389.1		c.2127-54T>C		intron	N/A	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29768 AN: 152072 Hom.: 6166 Cov.: 32

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.0756 AC: 102685 AN: 1358594 Hom.: 7777 AF XY: 0.0732 AC XY: 48634 AN XY: 664544

African (AFR) AF: 0.542 AC: 16526 AN: 30510

American (AMR) AF: 0.0879 AC: 2850 AN: 32426

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 977 AN: 23030

East Asian (EAS) AF: 0.0367 AC: 1291 AN: 35168

South Asian (SAS) AF: 0.0231 AC: 1719 AN: 74472

European-Finnish (FIN) AF: 0.0542 AC: 2477 AN: 45702

Middle Eastern (MID) AF: 0.0519 AC: 278 AN: 5360

European-Non Finnish (NFE) AF: 0.0677 AC: 71456 AN: 1055806

Other (OTH) AF: 0.0911 AC: 5111 AN: 56120

GnomAD4 genome AF: 0.196 AC: 29864 AN: 152190 Hom.: 6199 Cov.: 32 AF XY: 0.190 AC XY: 14104 AN XY: 74398

African (AFR) AF: 0.528 AC: 21906 AN: 41458

American (AMR) AF: 0.118 AC: 1801 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3466

East Asian (EAS) AF: 0.0345 AC: 179 AN: 5190

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4832

European-Finnish (FIN) AF: 0.0538 AC: 571 AN: 10618

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0709 AC: 4824 AN: 68014

Other (OTH) AF: 0.130 AC: 274 AN: 2112

Alfa AF: 0.104 Hom.: 8083

Bravo AF: 0.214

Asia WGS AF: 0.105 AC: 366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.6
DANN	Benign	0.40
PhyloP100		-0.085
Mutation Taster		=100/0	polymorphism (auto)

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: rs2066808; hg19: chr12-56737973;