2-112917677-C-T

Variant names:

• chr2-112917677-C-T
• rs765216544
• NM_014439.4:c.308C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_014439.4(IL37):​c.308C>T​(p.Ala103Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000802 in 1,608,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: IL37 NM_014439.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.442
• Publications: 2 publications found

Genes affected

IL37 (HGNC:15563): (interleukin 37) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine can bind to, and may be a ligand for interleukin 18 receptor (IL18R1/IL-1Rrp). This cytokine also binds to interleukin 18 binding protein (IL18BP), an inhibitory binding protein of interleukin 18 (IL18), and subsequently forms a complex with IL18 receptor beta subunit, and through which it inhibits the activity of IL18. This gene along with eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Five alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

IL37 Gene-Disease associations (from GenCC):

• inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02517429).
• BP6: Variant 2-112917677-C-T is Benign according to our data. Variant chr2-112917677-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2354250.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014439.4. 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
	IL37	NM_014439.4	MANE Select	c.308C>T	p.Ala103Val	missense	Exon 5 of 6	NP_055254.2
	IL37	NM_173202.2		c.245C>T	p.Ala82Val	missense	Exon 4 of 5	NP_775294.1	Q9NZH6-4
	IL37	NM_173205.2		c.230C>T	p.Ala77Val	missense	Exon 3 of 4	NP_775297.1	Q9NZH6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL37	ENST00000263326.8	TSL:1 MANE Select	c.308C>T	p.Ala103Val	missense	Exon 5 of 6	ENSP00000263326.3	Q9NZH6-1
	IL37	ENST00000352179.7	TSL:1	c.245C>T	p.Ala82Val	missense	Exon 3 of 4	ENSP00000263327.3	Q9NZH6-4
	IL37	ENST00000311328.2	TSL:1	c.230C>T	p.Ala77Val	missense	Exon 3 of 4	ENSP00000309883.2	Q9NZH6-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 246998 AF XY: 0.000105

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000844 AC: 123 AN: 1456742 Hom.: 0 Cov.: 31 AF XY: 0.0000856 AC XY: 62 AN XY: 724564

African (AFR) AF: 0.0000603 AC: 2 AN: 33166

American (AMR) AF: 0.0000228 AC: 1 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 44 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.0000577 AC: 64 AN: 1109886

Other (OTH) AF: 0.000150 AC: 9 AN: 60160

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000940 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.64
DANN	Benign	0.76
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.44
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.050
Sift	Benign	0.29	T
Sift4G	Benign	0.30	T
Polyphen		0.13	B
Vest4		0.040
MVP		0.072
MPC		0.089
ClinPred		0.012	T
GERP RS		-5.8
Varity_R		0.11
gMVP		0.13
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765216544; hg19: chr2-113675254; COSMIC: COSV106094142;