rs2066811

Positions:

• chr12-56349213-T-C
• chr12-56349213-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 15/20 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

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT2. . Gene score misZ 2.5952 (greater than the threshold 3.09). Trascript score misZ 3.6431 (greater than threshold 3.09). GenCC has associacion of gene with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, pseudo-TORCH syndrome 3.
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT2	NM_005419.4	c.1390A>G	p.Ile464Val	missense_variant	16/24	ENST00000314128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT2	ENST00000314128.9	c.1390A>G	p.Ile464Val	missense_variant	16/24	1	NM_005419.4	P2

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

GnomAD3 exomes AF: 0.0169 AC: 4251 AN: 251478 Hom.: 355 AF XY: 0.0128 AC XY: 1745 AN XY: 135912

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 SAS exome AF: 0.000359

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

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000897

Gnomad4 OTH exome AF: 0.0152

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

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0121 Hom.: 218

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.13
Sift	Benign	0.80	T;T
Sift4G	Benign	0.94	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2066811; hg19: chr12-56742997; COSMIC: COSV58475270; COSMIC: COSV58475270;