1-206768671-T-C

Variant names:

• chr1-206768671-T-C
• rs2102436707
• NM_000572.3:c.502A>G

Variant summary

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

The NM_000572.3(IL10):​c.502A>G​(p.Ile168Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I168K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IL10 NM_000572.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

Genes affected

IL10 (HGNC:5962): (interleukin 10) The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. Mutations in this gene are associated with an increased susceptibility to HIV-1 infection and rheumatoid arthritis. [provided by RefSeq, May 2020]

IL10 Gene-Disease associations (from GenCC):

• IL10-related early-onset inflammatory bowel disease

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

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_000572.3. 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
	IL10	NM_000572.3	MANE Select	c.502A>G	p.Ile168Val	missense	Exon 5 of 5	NP_000563.1	P22301
	IL10	NM_001382624.1		c.247A>G	p.Ile83Val	missense	Exon 3 of 3	NP_001369553.1	A0A286YEX3
	IL10	NR_168466.1		n.799A>G		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10	ENST00000423557.1	TSL:1 MANE Select	c.502A>G	p.Ile168Val	missense	Exon 5 of 5	ENSP00000412237.1	P22301
	IL10	ENST00000659065.2		c.385A>G	p.Ile129Val	missense	Exon 7 of 7	ENSP00000499588.1	A0A590UK12
	IL10	ENST00000659642.2		c.385A>G	p.Ile129Val	missense	Exon 6 of 6	ENSP00000499509.1	A0A590UK12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456742 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 725036

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107366

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inflammatory bowel disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.24
Sift	Benign	0.036	D
Sift4G	Uncertain	0.018	D
Polyphen		0.13	B
Vest4		0.17
MutPred		0.64		Gain of catalytic residue at I168 (P = 0.0675)
MVP		0.88
MPC		0.15
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.55
gMVP		0.39
Mutation Taster		=74/26	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: rs2102436707; hg19: chr1-206942016;