rs2066807

Variant names:

• chr12-56346898-C-G
• rs2066807
• NM_005419.4:c.1782G>C

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.1782G>C​(p.Met594Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,614,160 control chromosomes in the GnomAD database, including 3,148 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M594V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 31)
  • Exomes 𝑓: 0.060 (2922 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.51
• Publications: 107 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=0.0018221736).
• BP6: Variant 12-56346898-C-G is Benign according to our data. Variant chr12-56346898-C-G is described in ClinVar as Benign. ClinVar VariationId is 403493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0668 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.1782G>C	p.Met594Ile	missense	Exon 20 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.1770G>C	p.Met590Ile	missense	Exon 20 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.1761G>C	p.Met587Ile	missense	Exon 19 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.1782G>C	p.Met594Ile	missense	Exon 20 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.712G>C		non_coding_transcript_exon	Exon 7 of 11
	STAT2	ENST00000922389.1		c.1806G>C	p.Met602Ile	missense	Exon 20 of 24	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6973 AN: 152168 Hom.: 222 Cov.: 31

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.0343

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.0537

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0490 AC: 12319 AN: 251374 AF XY: 0.0485

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.0541

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.0286

Gnomad FIN exome AF: 0.0557

Gnomad NFE exome AF: 0.0644

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0595 AC: 86991 AN: 1461874 Hom.: 2922 Cov.: 32 AF XY: 0.0590 AC XY: 42923 AN XY: 727242

African (AFR) AF: 0.00941 AC: 315 AN: 33478

American (AMR) AF: 0.0536 AC: 2396 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 637 AN: 26136

East Asian (EAS) AF: 0.0360 AC: 1428 AN: 39700

South Asian (SAS) AF: 0.0223 AC: 1927 AN: 86258

European-Finnish (FIN) AF: 0.0546 AC: 2917 AN: 53416

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5768

European-Non Finnish (NFE) AF: 0.0665 AC: 73936 AN: 1111998

Other (OTH) AF: 0.0546 AC: 3300 AN: 60396

GnomAD4 genome AF: 0.0459 AC: 6992 AN: 152286 Hom.: 226 Cov.: 31 AF XY: 0.0450 AC XY: 3354 AN XY: 74456

African (AFR) AF: 0.0111 AC: 461 AN: 41560

American (AMR) AF: 0.0543 AC: 830 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3468

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5178

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4828

European-Finnish (FIN) AF: 0.0537 AC: 570 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0685 AC: 4657 AN: 68028

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0630 Hom.: 278

Bravo AF: 0.0424

TwinsUK AF: 0.0672 AC: 249

ALSPAC AF: 0.0625 AC: 241

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0627 AC: 539

ExAC AF: 0.0481 AC: 5837

Asia WGS AF: 0.0750 AC: 259 AN: 3478

EpiCase AF: 0.0619

EpiControl AF: 0.0578

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	0.084
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.42
DANN	Benign	0.61
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.024	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.95	N
PhyloP100		-2.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.36
Sift	Benign	0.22	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.012
MutPred		0.23		Loss of disorder (P = 0.0713)
MPC		0.44
ClinPred		0.0038	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.044
gMVP		0.34
Mutation Taster		=99/1	polymorphism (auto)

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: rs2066807; hg19: chr12-56740682; COSMIC: COSV58474337; COSMIC: COSV58474337;