rs146115536

Variant names:

• chr12-56349466-G-A
• rs146115536
• NM_005419.4:c.1301C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-56349466-G-A
• chr12-56349466-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_005419.4(STAT2):​c.1301C>T​(p.Thr434Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T434R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.410
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2179882).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000184 (269/1461890) while in subpopulation EAS AF = 0.000327 (13/39700). AF 95% confidence interval is 0.000198. There are 0 homozygotes in GnomAdExome4. There are 120 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1301C>T	p.Thr434Met	missense	Exon 15 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.1289C>T	p.Thr430Met	missense	Exon 15 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.1280C>T	p.Thr427Met	missense	Exon 14 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.1301C>T	p.Thr434Met	missense	Exon 15 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.231C>T		non_coding_transcript_exon	Exon 2 of 11
	STAT2	ENST00000922389.1		c.1301C>T	p.Thr434Met	missense	Exon 15 of 24	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 20 AN: 251476 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 269 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74300

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (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	0.083
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.41
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.036	D
Sift4G	Benign	0.084	T
Polyphen		0.52	P
Vest4		0.26
MVP		0.78
MPC		0.57
ClinPred		0.045	T
GERP RS		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.53
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146115536; hg19: chr12-56743250; COSMIC: COSV58474059; COSMIC: COSV58474059;