rs2066819

Variant names:

• chr12-56356420-C-T
• rs2066819
• NM_005419.4:c.131+21G>A

Variant summary

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

The NM_005419.4(STAT2):​c.131+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,610,634 control chromosomes in the GnomAD database, including 3,110 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 0.046 (222 hom., cov: 31)
  • Exomes 𝑓: 0.059 (2888 hom.)
• Consequence: STAT2 NM_005419.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.805
• Publications: 38 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• pseudo-TORCH syndrome 3

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT2	NM_005419.4	c.131+21G>A		intron_variant	Intron 2 of 23	ENST00000314128.9	NP_005410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT2	ENST00000314128.9	c.131+21G>A		intron_variant	Intron 2 of 23	1	NM_005419.4	ENSP00000315768.4

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6935 AN: 152144 Hom.: 219 Cov.: 31

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.0194

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0683

Gnomad OTH AF: 0.0291

GnomAD2 exomes AF: 0.0488 AC: 12168 AN: 249138 AF XY: 0.0484

Gnomad AFR exome AF: 0.00912

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.0293

Gnomad FIN exome AF: 0.0556

Gnomad NFE exome AF: 0.0642

Gnomad OTH exome AF: 0.0441

GnomAD4 exome AF: 0.0594 AC: 86611 AN: 1458372 Hom.: 2888 Cov.: 32 AF XY: 0.0589 AC XY: 42712 AN XY: 725232

African (AFR) AF: 0.00816 AC: 272 AN: 33326

American (AMR) AF: 0.0531 AC: 2344 AN: 44148

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 630 AN: 26022

East Asian (EAS) AF: 0.0363 AC: 1442 AN: 39670

South Asian (SAS) AF: 0.0223 AC: 1914 AN: 85764

European-Finnish (FIN) AF: 0.0546 AC: 2914 AN: 53378

Middle Eastern (MID) AF: 0.0166 AC: 89 AN: 5346

European-Non Finnish (NFE) AF: 0.0664 AC: 73780 AN: 1110490

Other (OTH) AF: 0.0536 AC: 3226 AN: 60228

GnomAD4 genome AF: 0.0456 AC: 6947 AN: 152262 Hom.: 222 Cov.: 31 AF XY: 0.0446 AC XY: 3320 AN XY: 74450

African (AFR) AF: 0.0109 AC: 454 AN: 41554

American (AMR) AF: 0.0530 AC: 810 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.0339 AC: 176 AN: 5186

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4830

European-Finnish (FIN) AF: 0.0536 AC: 569 AN: 10606

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0684 AC: 4649 AN: 67998

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0535 Hom.: 61

Bravo AF: 0.0421

Asia WGS AF: 0.0670 AC: 231 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.63
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs2066819; hg19: chr12-56750204; COSMIC: COSV58477649; COSMIC: COSV58477649;