12-57099333-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003153.5(STAT6):c.1852A>G(p.Lys618Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT6 NM_003153.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

STAT6 (HGNC:11368): (signal transducer and activator of transcription 6) The protein encoded by this gene is a member of the STAT family of transcription factors. 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. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2) cells, expression of cell surface markers, and class switch of immunoglobulins. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAT6
• BP4: Computational evidence support a benign effect (MetaRNN=0.2120657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT6	NM_003153.5	c.1852A>G	p.Lys618Glu	missense_variant	16/22	ENST00000300134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT6	ENST00000300134.8	c.1852A>G	p.Lys618Glu	missense_variant	16/22	1	NM_003153.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.1852A>G (p.K618E) alteration is located in exon 16 (coding exon 15) of the STAT6 gene. This alteration results from a A to G substitution at nucleotide position 1852, causing the lysine (K) at amino acid position 618 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;T;.;T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.74	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	-0.90	N;.;N;N;.;N;.;.
MutationTaster	Benign	0.84	D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.2	N;N;N;N;N;N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.10	T;T;T;T;T;T;T;.
Sift4G	Benign	0.14	T;T;T;T;T;T;T;.
Polyphen		0.073	B;.;B;B;.;B;.;.
Vest4		0.21
MutPred		0.33		Loss of methylation at K618 (P = 0.0062);.;Loss of methylation at K618 (P = 0.0062);Loss of methylation at K618 (P = 0.0062);.;Loss of methylation at K618 (P = 0.0062);.;Loss of methylation at K618 (P = 0.0062);
MVP		0.92
MPC		0.72
ClinPred		0.68	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.81

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: chr12-57493116;