X-115017226-A-G

Variant names:

• chrX-115017226-A-G
• rs1602978685
• NM_000640.3:c.44T>C

Variant summary

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

The NM_000640.3(IL13RA2):​c.44T>C​(p.Leu15Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000218 in 917,655 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000022 (0 hom. 1 hem.)
• Consequence: IL13RA2 NM_000640.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

Genes affected

IL13RA2 (HGNC:5975): (interleukin 13 receptor subunit alpha 2) The protein encoded by this gene is closely related to Il13RA1, a subuint of the interleukin 13 receptor complex. This protein binds IL13 with high affinity, but lacks cytoplasmic domain, and does not appear to function as a signal mediator. It is reported to play a role in the internalization of IL13. [provided by RefSeq, Jul 2008]

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, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL13RA2	NM_000640.3	c.44T>C	p.Leu15Pro	missense_variant	Exon 2 of 10	ENST00000243213.2	NP_000631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL13RA2	ENST00000243213.2	c.44T>C	p.Leu15Pro	missense_variant	Exon 2 of 10	1	NM_000640.3	ENSP00000243213.1
IL13RA2	ENST00000371936.5	c.44T>C	p.Leu15Pro	missense_variant	Exon 3 of 11	5		ENSP00000361004.1
IL13RA2	ENST00000468224.1	n.348T>C		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000218 AC: 2 AN: 917655 Hom.: 0 Cov.: 18 AF XY: 0.00000375 AC XY: 1 AN XY: 266529

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: 0.00000294

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44T>C (p.L15P) alteration is located in exon 2 (coding exon 1) of the IL13RA2 gene. This alteration results from a T to C substitution at nucleotide position 44, causing the leucine (L) at amino acid position 15 to be replaced by a proline (P). 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	Benign	0.18
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.44	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.68		Loss of stability (P = 0.064);Loss of stability (P = 0.064);
MVP		0.31
MPC		1.0
ClinPred		0.60	D
GERP RS		3.9
Varity_R		0.69
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1602978685; hg19: chrX-114251789;