16-11254849-C-G

Variant names:

• chr16-11254849-C-G
• rs11549428
• NM_003745.2:c.630G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003745.2(SOCS1):​c.630G>C​(p.Gln210His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,478,218 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q210R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (69 hom.)
• Consequence: SOCS1 NM_003745.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.92
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009278804).
• BP6: Variant 16-11254849-C-G is Benign according to our data. Variant chr16-11254849-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 135275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00534 (813/152302) while in subpopulation NFE AF = 0.00922 (627/68018). AF 95% confidence interval is 0.00862. There are 4 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 813 AD gene.

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.630G>C	p.Gln210His	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.630G>C	p.Gln210His	missense	Exon 2 of 2	ENSP00000329418.2	O15524
	RMI2	ENST00000572173.1	TSL:1	c.-516+5071C>G		intron	N/A	ENSP00000461206.1	Q96E14-2
	SOCS1	ENST00000644787.2		c.630G>C	p.Gln210His	missense	Exon 1 of 1	ENSP00000496577.1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 813 AN: 152184 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00922

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00498 AC: 642 AN: 128918 AF XY: 0.00487

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.000771

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00421

GnomAD4 exome AF: 0.00925 AC: 12270 AN: 1325916 Hom.: 69 Cov.: 32 AF XY: 0.00882 AC XY: 5773 AN XY: 654216

African (AFR) AF: 0.00151 AC: 39 AN: 25874

American (AMR) AF: 0.00142 AC: 29 AN: 20414

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 10 AN: 18660

East Asian (EAS) AF: 0.00 AC: 0 AN: 32574

South Asian (SAS) AF: 0.000632 AC: 41 AN: 64904

European-Finnish (FIN) AF: 0.00234 AC: 116 AN: 49476

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5222

European-Non Finnish (NFE) AF: 0.0111 AC: 11753 AN: 1054722

Other (OTH) AF: 0.00520 AC: 281 AN: 54070

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152302 Hom.: 4 Cov.: 33 AF XY: 0.00450 AC XY: 335 AN XY: 74488

African (AFR) AF: 0.00241 AC: 100 AN: 41572

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10614

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00922 AC: 627 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00815 Hom.: 2

Bravo AF: 0.00571

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00229 AC: 10

ESP6500EA AF: 0.00854 AC: 73

ExAC AF: 0.00435 AC: 525

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.059
Sift	Benign	0.068	T
Sift4G	Benign	0.065	T
Polyphen		0.97	D
Vest4		0.14
MutPred		0.12		Gain of helix (P = 0.0325)
MVP		0.66
MPC		1.5
ClinPred		0.012	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.46
Mutation Taster		=83/17	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: rs11549428; hg19: chr16-11348706; COSMIC: COSV59659165;