12-56343467-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005419.4(STAT2):c.2478G>T(p.Gln826His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,614,160 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (77 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.339

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 where missense usually causes diseases, STAT2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004781902).
• BP6: Variant 12-56343467-C-A is Benign according to our data. Variant chr12-56343467-C-A is described in ClinVar as [Benign]. Clinvar id is 475692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56343467-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00788 (1200/152292) while in subpopulation NFE AF= 0.0114 (774/68022). AF 95% confidence interval is 0.0107. There are 10 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT2	NM_005419.4	c.2478G>T	p.Gln826His	missense_variant	24/24	ENST00000314128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT2	ENST00000314128.9	c.2478G>T	p.Gln826His	missense_variant	24/24	1	NM_005419.4	P2

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152174 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00789 AC: 1985 AN: 251442 Hom.: 13 AF XY: 0.00790 AC XY: 1073 AN XY: 135886

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00902 AC: 13184 AN: 1461868 Hom.: 77 Cov.: 31 AF XY: 0.00906 AC XY: 6588 AN XY: 727232

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.0345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00208

Gnomad4 FIN exome AF: 0.00790

Gnomad4 NFE exome AF: 0.00957

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00788 AC: 1200 AN: 152292 Hom.: 10 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74472

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.0378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0116 Hom.: 35

Bravo AF: 0.00721

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.00769 AC: 934

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0128

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

STAT2: BP4, BS1, BS2 -

STAT2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.0060	B;.
Vest4		0.14
MutPred		0.14		Gain of catalytic residue at N827 (P = 0.051);.;
MVP		0.35
MPC		0.40
ClinPred		0.0072	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2229363; hg19: chr12-56737251;