12-93573027-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001270471.2(SOCS2):​c.130G>C​(p.Gly44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOCS2 NM_001270471.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06635237).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270471.2. 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
	SOCS2	NM_001270471.2	MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 1 of 2	NP_001257400.1	O14508
	SOCS2	NM_001270467.2		c.130G>C	p.Gly44Arg	missense	Exon 2 of 3	NP_001257396.1	O14508
	SOCS2	NM_001270468.2		c.130G>C	p.Gly44Arg	missense	Exon 2 of 3	NP_001257397.1	O14508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOCS2	ENST00000551556.2	TSL:1 MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 1 of 2	ENSP00000449227.1	O14508
	SOCS2	ENST00000340600.6	TSL:1	c.130G>C	p.Gly44Arg	missense	Exon 2 of 3	ENSP00000339428.2	O14508
	SOCS2	ENST00000549122.5	TSL:1	c.130G>C	p.Gly44Arg	missense	Exon 2 of 3	ENSP00000447161.1	O14508

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412972 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32690

American (AMR) AF: 0.00 AC: 0 AN: 38354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 37556

South Asian (SAS) AF: 0.00 AC: 0 AN: 80946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091812

Other (OTH) AF: 0.00 AC: 0 AN: 58780

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.8
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.093
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.043
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.34		Gain of solvent accessibility (P = 0.0456)
MVP		0.18
MPC		0.71
ClinPred		0.057	T
GERP RS		-2.2
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.14
gMVP		0.60
Mutation Taster		=76/24	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: rs769795840; hg19: chr12-93966803;