rs2229363

Variant names:

• chr12-56343467-C-A
• rs2229363
• NM_005419.4:c.2478G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-56343467-C-A
• chr12-56343467-C-G
• chr12-56343467-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005419.4(STAT2):​c.2478G>T​(p.Gln826His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,614,160 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (77 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.339
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004781902).
• BP6: Variant 12-56343467-C-A is Benign according to our data. Variant chr12-56343467-C-A is described in ClinVar as Benign. ClinVar VariationId is 475692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00788 (1200/152292) while in subpopulation NFE AF = 0.0114 (774/68022). AF 95% confidence interval is 0.0107. There are 10 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.2478G>T	p.Gln826His	missense	Exon 24 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.2466G>T	p.Gln822His	missense	Exon 24 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.2457G>T	p.Gln819His	missense	Exon 23 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.2478G>T	p.Gln826His	missense	Exon 24 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.1408G>T		non_coding_transcript_exon	Exon 11 of 11
	STAT2	ENST00000922389.1		c.2502G>T	p.Gln834His	missense	Exon 24 of 24	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152174 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00789 AC: 1985 AN: 251442 AF XY: 0.00790

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00902 AC: 13184 AN: 1461868 Hom.: 77 Cov.: 31 AF XY: 0.00906 AC XY: 6588 AN XY: 727232

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00528 AC: 236 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 901 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86258

European-Finnish (FIN) AF: 0.00790 AC: 422 AN: 53420

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5764

European-Non Finnish (NFE) AF: 0.00957 AC: 10646 AN: 1111998

Other (OTH) AF: 0.0104 AC: 630 AN: 60394

GnomAD4 genome AF: 0.00788 AC: 1200 AN: 152292 Hom.: 10 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74472

African (AFR) AF: 0.00149 AC: 62 AN: 41556

American (AMR) AF: 0.00798 AC: 122 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 774 AN: 68022

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.0106 Hom.: 44

Bravo AF: 0.00721

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.00769 AC: 934

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0128

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.34
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.082
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0060	B
Vest4		0.14
MutPred		0.14		Gain of catalytic residue at N827 (P = 0.051)
MVP		0.35
MPC		0.40
ClinPred		0.0072	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.24
Mutation Taster		=93/7	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: rs2229363; hg19: chr12-56737251;