2-190978863-G-C

Position:

• chr2-190978863-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_007315.4(STAT1):​c.1866C>G​(p.Asn622Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N622N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.783

Genes affected

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) 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. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT1. . Gene score misZ 5.1492 (greater than the threshold 3.09). Trascript score misZ 7.0181 (greater than threshold 3.09). GenCC has associacion of gene with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3767792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.1866C>G	p.Asn622Lys	missense_variant	21/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.1866C>G	p.Asn622Lys	missense_variant	21/25	1	NM_007315.4	P4

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	0.19
BayesDel_addAF	Benign	-0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.026
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;D;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	2.0	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.0090	B;B;B;.
Vest4		0.39
MutPred		0.47		Gain of methylation at N622 (P = 0.0056);Gain of methylation at N622 (P = 0.0056);Gain of methylation at N622 (P = 0.0056);.;
MVP		0.88
MPC		1.7
ClinPred		0.76	D
GERP RS		-7.9
Varity_R		0.32
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-191843589;