rs2020854

Variant names:

• chr12-56349583-T-C
• rs2020854
• NM_005419.4:c.1257+6A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-56349583-T-C
• chr12-56349583-T-A

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.1257+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,613,970 control chromosomes in the GnomAD database, including 14,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (6143 hom., cov: 31)
  • Exomes 𝑓: 0.076 (8386 hom.)
• Consequence: STAT2 NM_005419.4 splice_region, intron
• Scores: Splicing: ADA: 0.000003225
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.514
• Publications: 37 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 (BayesDel_noAF=-0.81).
• BP6: Variant 12-56349583-T-C is Benign according to our data. Variant chr12-56349583-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 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.1257+6A>G		splice_region intron	N/A	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.1245+6A>G		splice_region intron	N/A	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.1236+6A>G		splice_region intron	N/A	NP_001372043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT2	ENST00000314128.9	TSL:1 MANE Select	c.1257+6A>G		splice_region intron	N/A	ENSP00000315768.4	P52630-3
	STAT2	ENST00000556539.5	TSL:1	n.187+6A>G		splice_region intron	N/A
	STAT2	ENST00000922389.1		c.1257+6A>G		splice_region intron	N/A	ENSP00000592448.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29663 AN: 151962 Hom.: 6111 Cov.: 31

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.0347

Gnomad SAS AF: 0.0212

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0710

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.0894 AC: 22474 AN: 251482 AF XY: 0.0785

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.0821

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.0298

Gnomad FIN exome AF: 0.0557

Gnomad NFE exome AF: 0.0664

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0757 AC: 110639 AN: 1461890 Hom.: 8386 Cov.: 33 AF XY: 0.0730 AC XY: 53104 AN XY: 727248

African (AFR) AF: 0.539 AC: 18061 AN: 33480

American (AMR) AF: 0.0858 AC: 3839 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 1128 AN: 26136

East Asian (EAS) AF: 0.0365 AC: 1451 AN: 39700

South Asian (SAS) AF: 0.0234 AC: 2022 AN: 86258

European-Finnish (FIN) AF: 0.0547 AC: 2922 AN: 53420

Middle Eastern (MID) AF: 0.0499 AC: 288 AN: 5768

European-Non Finnish (NFE) AF: 0.0678 AC: 75448 AN: 1112008

Other (OTH) AF: 0.0907 AC: 5480 AN: 60396

GnomAD4 genome AF: 0.196 AC: 29758 AN: 152080 Hom.: 6143 Cov.: 31 AF XY: 0.189 AC XY: 14049 AN XY: 74344

African (AFR) AF: 0.526 AC: 21796 AN: 41432

American (AMR) AF: 0.118 AC: 1796 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.0346 AC: 179 AN: 5172

South Asian (SAS) AF: 0.0210 AC: 101 AN: 4814

European-Finnish (FIN) AF: 0.0539 AC: 571 AN: 10602

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0710 AC: 4828 AN: 67992

Other (OTH) AF: 0.131 AC: 277 AN: 2114

Alfa AF: 0.109 Hom.: 3734

Bravo AF: 0.213

Asia WGS AF: 0.104 AC: 361 AN: 3478

EpiCase AF: 0.0647

EpiControl AF: 0.0612

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.7
DANN	Benign	0.61
PhyloP100		-0.51
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000032
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.050		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: rs2020854; hg19: chr12-56743367; COSMIC: COSV58475889; COSMIC: COSV58475889;