chr6-137154943-T-G

Position:

• chr6-137154943-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_052962.3(IL22RA2):​c.470A>C​(p.Glu157Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000123 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: IL22RA2 NM_052962.3 missense, splice_region
• Scores: Splicing: ADA: 0.05548
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

Genes affected

IL22RA2 (HGNC:14901): (interleukin 22 receptor subunit alpha 2) This gene encodes a member of the class II cytokine receptor family. The encoded soluble protein specifically binds to and inhibits interleukin 22 activity by blocking the interaction of interleukin 22 with its cell surface receptor. The encoded protein may be important in the regulation of inflammatory response, and has been implicated in the regulation of tumorigenesis in the colon. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL22RA2	NM_052962.3	c.470A>C	p.Glu157Ala	missense_variant, splice_region_variant	5/7	ENST00000296980.7
IL22RA2	NM_181309.2	c.374A>C	p.Glu125Ala	missense_variant, splice_region_variant	4/6
IL22RA2	NM_181310.2	c.374A>C	p.Glu125Ala	missense_variant, splice_region_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL22RA2	ENST00000296980.7	c.470A>C	p.Glu157Ala	missense_variant, splice_region_variant	5/7	1	NM_052962.3
IL22RA2	ENST00000349184.9	c.374A>C	p.Glu125Ala	missense_variant, splice_region_variant	4/6	1		P1
IL22RA2	ENST00000339602.3	c.374A>C	p.Glu125Ala	missense_variant, splice_region_variant	4/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727144

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: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 23, 2023

The c.470A>C (p.E157A) alteration is located in exon 5 (coding exon 4) of the IL22RA2 gene. This alteration results from a A to C substitution at nucleotide position 470, causing the glutamic acid (E) at amino acid position 157 to be replaced by an alanine (A). 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Pathogenic	3.3	.;M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.96	D;D;D
Vest4		0.73
MutPred		0.76		.;Gain of MoRF binding (P = 0.0699);.;
MVP		0.53
MPC		0.044
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.055
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.030		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: rs1179817502; hg19: chr6-137476080;