12-56355758-G-T

Variant names:

• chr12-56355758-G-T
• NM_005419.4:c.331C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005419.4(STAT2):​c.331C>A​(p.Leu111Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STAT2 NM_005419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20778874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT2	NM_005419.4	c.331C>A	p.Leu111Ile	missense_variant	Exon 4 of 24	ENST00000314128.9	NP_005410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT2	ENST00000314128.9	c.331C>A	p.Leu111Ile	missense_variant	Exon 4 of 24	1	NM_005419.4	ENSP00000315768.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331C>A (p.L111I) alteration is located in exon 4 (coding exon 3) of the STAT2 gene. This alteration results from a C to A substitution at nucleotide position 331, causing the leucine (L) at amino acid position 111 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.42	T;T;D
Polyphen		0.96	D;.;P
Vest4		0.34
MutPred		0.60		Loss of stability (P = 0.0852);.;.;
MVP		0.38
MPC		0.93
ClinPred		0.69	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.070

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56749542;