12-93573027-G-A

Variant names:

• chr12-93573027-G-A
• rs769795840
• NM_001270471.2:c.130G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001270471.2(SOCS2):​c.130G>A​(p.Gly44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SOCS2 NM_001270471.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0930

Genes affected

SOCS2 (HGNC:19382): (suppressor of cytokine signaling 2) This gene encodes a member of the suppressor of cytokine signaling (SOCS) family. SOCS family members are cytokine-inducible negative regulators of cytokine receptor signaling via the Janus kinase/signal transducer and activation of transcription pathway (the JAK/STAT pathway). SOCS family proteins interact with major molecules of signaling complexes to block further signal transduction, in part, by proteasomal depletion of receptors or signal-transducing proteins via ubiquitination. The expression of this gene can be induced by a subset of cytokines, including erythropoietin, GM-CSF, IL10, interferon (IFN)-gamma and by cytokine receptors such as growth horomone receptor. The protein encoded by this gene interacts with the cytoplasmic domain of insulin-like growth factor-1 receptor (IGF1R) and is thought to be involved in the regulation of IGF1R mediated cell signaling. This gene has pseudogenes on chromosomes 20 and 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05431038).
• BP6: Variant 12-93573027-G-A is Benign according to our data. Variant chr12-93573027-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3321393.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOCS2	NM_001270471.2	c.130G>A	p.Gly44Ser	missense_variant	Exon 1 of 2	ENST00000551556.2	NP_001257400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOCS2	ENST00000551556.2	c.130G>A	p.Gly44Ser	missense_variant	Exon 1 of 2	1	NM_001270471.2	ENSP00000449227.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412972 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 699394

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: 0.0000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000861 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 25, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T;T;T;T;T;T;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.59	.;.;.;T;.;T;T;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.054	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N;N;N;.;N;N;.;.;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.5	N;N;N;N;N;.;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.52	T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;.;.;B
Vest4		0.069
MutPred		0.39		Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);Gain of phosphorylation at G44 (P = 0.049);
MVP		0.21
MPC		0.60
ClinPred		0.059	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.14
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs769795840; hg19: chr12-93966803;