16-11254862-G-C

Variant names:

• chr16-11254862-G-C
• rs769665959
• NM_003745.2:c.617C>G

Variant summary

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

The NM_003745.2(SOCS1):​c.617C>G​(p.Ser206Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S206F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOCS1 NM_003745.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13
• Publications: 2 publications found

Genes affected

SOCS1 (HGNC:19383): (suppressor of cytokine signaling 1) This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including IL2, IL3 erythropoietin (EPO), CSF2/GM-CSF, and interferon (IFN)-gamma. The protein encoded by this gene functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. Knockout studies in mice suggested the role of this gene as a modulator of IFN-gamma action, which is required for normal postnatal growth and survival. [provided by RefSeq, Jul 2008]

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

LOC105371082 (HGNC:):

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_003745.2. 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
	SOCS1	NM_003745.2	MANE Select	c.617C>G	p.Ser206Cys	missense	Exon 2 of 2	NP_003736.1	Q4JHT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOCS1	ENST00000332029.4	TSL:1 MANE Select	c.617C>G	p.Ser206Cys	missense	Exon 2 of 2	ENSP00000329418.2	O15524
	RMI2	ENST00000572173.1	TSL:1	c.-516+5084G>C		intron	N/A	ENSP00000461206.1	Q96E14-2
	SOCS1	ENST00000644787.2		c.617C>G	p.Ser206Cys	missense	Exon 1 of 1	ENSP00000496577.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 134580 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000150 AC: 2 AN: 1337226 Hom.: 0 Cov.: 32 AF XY: 0.00000151 AC XY: 1 AN XY: 661166

African (AFR) AF: 0.00 AC: 0 AN: 26172

American (AMR) AF: 0.00 AC: 0 AN: 21230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 32736

South Asian (SAS) AF: 0.0000150 AC: 1 AN: 66566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5270

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061406

Other (OTH) AF: 0.00 AC: 0 AN: 54658

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Benign	0.037	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.46		Loss of disorder (P = 2e-04)
MVP		0.57
MPC		1.8
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.49
Mutation Taster		=77/23	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: rs769665959; hg19: chr16-11348719;