12-93575159-G-T

Variant names:

• chr12-93575159-G-T
• rs755618401
• NM_001270471.2:c.577G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001270471.2(SOCS2):​c.577G>T​(p.Glu193*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,395,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SOCS2 NM_001270471.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.577G>T	p.Glu193*	stop_gained	Exon 2 of 2	NP_001257400.1	O14508
	SOCS2	NM_001270467.2		c.577G>T	p.Glu193*	stop_gained	Exon 3 of 3	NP_001257396.1	O14508
	SOCS2	NM_001270468.2		c.577G>T	p.Glu193*	stop_gained	Exon 3 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.577G>T	p.Glu193*	stop_gained	Exon 2 of 2	ENSP00000449227.1	O14508
	SOCS2	ENST00000340600.6	TSL:1	c.577G>T	p.Glu193*	stop_gained	Exon 3 of 3	ENSP00000339428.2	O14508
	SOCS2	ENST00000549122.5	TSL:1	c.577G>T	p.Glu193*	stop_gained	Exon 3 of 3	ENSP00000447161.1	O14508

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1395926 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689370

African (AFR) AF: 0.00 AC: 0 AN: 30808

American (AMR) AF: 0.00 AC: 0 AN: 31272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21754

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39230

South Asian (SAS) AF: 0.00 AC: 0 AN: 74476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084256

Other (OTH) AF: 0.00 AC: 0 AN: 57552

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
Vest4		0.79
GERP RS		5.8
PromoterAI		-0.014	Neutral
Mutation Taster		=8/192	disease causing

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: rs755618401; hg19: chr12-93968935;