chr12-56355514-G-A

Variant names:

• chr12-56355514-G-A
• rs1264238680
• NM_005419.4:c.400C>T

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.400C>T​(p.Leu134Phe) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L134L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70
• Publications: 2 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: 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=0.16917366).

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.400C>T	p.Leu134Phe	missense	Exon 5 of 24	NP_005410.1	P52630-3
	STAT2	NM_198332.2		c.388C>T	p.Leu130Phe	missense	Exon 5 of 24	NP_938146.1	P52630-4
	STAT2	NM_001385114.1		c.400C>T	p.Leu134Phe	missense	Exon 5 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.400C>T	p.Leu134Phe	missense	Exon 5 of 24	ENSP00000315768.4	P52630-3
	STAT2	ENST00000922389.1		c.400C>T	p.Leu134Phe	missense	Exon 5 of 24	ENSP00000592448.1
	STAT2	ENST00000960656.1		c.400C>T	p.Leu134Phe	missense	Exon 5 of 24	ENSP00000630715.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	0.087
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.7
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Benign	0.088	T
Sift4G	Benign	0.21	T
Polyphen		0.96	P
Vest4		0.022
MutPred		0.41		Loss of helix (P = 0.0017)
MVP		0.76
MPC		0.44
ClinPred		0.49	T
GERP RS		4.0
Varity_R		0.047
gMVP		0.053
Mutation Taster		=99/1	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: rs1264238680; hg19: chr12-56749298; COSMIC: COSV106441431; COSMIC: COSV106441431;