NM_005419.4:c.1390A>G

Variant names:

• chr12-56349213-T-C
• rs2066811
• NM_005419.4:c.1390A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005419.4(STAT2):​c.1390A>G​(p.Ile464Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,020 control chromosomes in the GnomAD database, including 1,543 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (811 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (732 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.190
• Publications: 19 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=0.0015448928).
• BP6: Variant 12-56349213-T-C is Benign according to our data. Variant chr12-56349213-T-C is described in ClinVar as Benign. ClinVar VariationId is 475689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 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.1390A>G	p.Ile464Val	missense	Exon 16 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.1378A>G	p.Ile460Val	missense	Exon 16 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.1369A>G	p.Ile457Val	missense	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.1390A>G	p.Ile464Val	missense	Exon 16 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.320A>G		non_coding_transcript_exon	Exon 3 of 11
	STAT2	ENST00000922389.1		c.1390A>G	p.Ile464Val	missense	Exon 16 of 24	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9056 AN: 152010 Hom.: 810 Cov.: 31

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.0397

GnomAD2 exomes AF: 0.0169 AC: 4251 AN: 251478 AF XY: 0.0128

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00676 AC: 9879 AN: 1461892 Hom.: 732 Cov.: 32 AF XY: 0.00590 AC XY: 4293 AN XY: 727246

African (AFR) AF: 0.201 AC: 6742 AN: 33480

American (AMR) AF: 0.0170 AC: 759 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 358 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.000897 AC: 998 AN: 1112010

Other (OTH) AF: 0.0152 AC: 921 AN: 60396

GnomAD4 genome AF: 0.0596 AC: 9062 AN: 152128 Hom.: 811 Cov.: 31 AF XY: 0.0578 AC XY: 4300 AN XY: 74370

African (AFR) AF: 0.200 AC: 8316 AN: 41478

American (AMR) AF: 0.0333 AC: 509 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 67982

Other (OTH) AF: 0.0393 AC: 83 AN: 2112

Alfa AF: 0.0230 Hom.: 604

Bravo AF: 0.0683

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.201 AC: 885

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.0200 AC: 2429

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.4
DANN	Benign	0.81
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.19
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.13
Sift	Benign	0.80	T
Sift4G	Benign	0.94	T
Polyphen		0.16	B
Vest4		0.030
MPC		0.34
ClinPred		0.0044	T
GERP RS		2.9
Varity_R		0.035
gMVP		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2066811; hg19: chr12-56742997; COSMIC: COSV58475270; COSMIC: COSV58475270;