chr12-93575159-G-A

Position:

• chr12-93575159-G-A

Variant summary

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

The NM_001270471.2(SOCS2):​c.577G>A​(p.Glu193Lys) variant causes a missense change involving the alteration of a 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOCS2 NM_001270471.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39786327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOCS2	NM_001270471.2	c.577G>A	p.Glu193Lys	missense_variant	2/2	ENST00000551556.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOCS2	ENST00000551556.2	c.577G>A	p.Glu193Lys	missense_variant	2/2	1	NM_001270471.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395924 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689370

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.577G>A (p.E193K) alteration is located in exon 3 (coding exon 2) of the SOCS2 gene. This alteration results from a G to A substitution at nucleotide position 577, causing the glutamic acid (E) at amino acid position 193 to be replaced by a lysine (K). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;.;.;D;.
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.40	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;D;D;.;D
REVEL	Benign	0.18
Sift	Uncertain	0.016	D;D;D;D;.;D
Sift4G	Benign	0.090	T;T;T;T;T;T
Polyphen		0.92	P;P;P;P;P;P
Vest4		0.34
MutPred		0.62		Gain of methylation at E193 (P = 0.0135);Gain of methylation at E193 (P = 0.0135);Gain of methylation at E193 (P = 0.0135);Gain of methylation at E193 (P = 0.0135);Gain of methylation at E193 (P = 0.0135);Gain of methylation at E193 (P = 0.0135);
MVP		0.59
MPC		0.78
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.59

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: rs755618401; hg19: chr12-93968935;