12-56343467-C-G

Variant names:

• chr12-56343467-C-G
• rs2229363
• NM_005419.4:c.2478G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005419.4(STAT2):​c.2478G>C​(p.Gln826His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• pseudo-TORCH syndrome 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12945357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT2	NM_005419.4	c.2478G>C	p.Gln826His	missense_variant	Exon 24 of 24	ENST00000314128.9	NP_005410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT2	ENST00000314128.9	c.2478G>C	p.Gln826His	missense_variant	Exon 24 of 24	1	NM_005419.4	ENSP00000315768.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		0.34
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.083
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		0.093	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.24
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs2229363; hg19: chr12-56737251;