Genetic Variant NM_000640.3:c.1091G>A (chrX-115005222-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000640.3(IL13RA2):c.1091G>A(p.Arg364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,063,822 control chromosomes in the GnomAD database, including 1 homozygotes. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.00012 ( 1 hom. 28 hem. )

Consequence

IL13RA2
NM_000640.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0110

Publications

4 publications found

Variant links:

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]

IL13RA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038280874).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000640.3. 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
	IL13RA2	NM_000640.3	MANE Select	c.1091G>A	p.Arg364His	missense	Exon 9 of 10	NP_000631.1	Q14627

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL13RA2	ENST00000243213.2	TSL:1 MANE Select	c.1091G>A	p.Arg364His	missense	Exon 9 of 10	ENSP00000243213.1	Q14627
IL13RA2	ENST00000371936.5	TSL:5	c.1091G>A	p.Arg364His	missense	Exon 10 of 11	ENSP00000361004.1	Q14627
IL13RA2	ENST00000958003.1		c.1091G>A	p.Arg364His	missense	Exon 9 of 10	ENSP00000628062.1

Frequencies

GnomAD3 genomes

AF:

0.0000799

AC:

AN:

112693

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.000363

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000937

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

182563

AF XY:

0.0000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000736

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000723

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000124

AC:

118

AN:

951129

Hom.:

Cov.:

AF XY:

0.0000989

AC XY:

AN XY:

283015

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23592

American (AMR)

AF:

0.0000572

AC:

AN:

34979

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18474

East Asian (EAS)

AF:

0.00

AC:

AN:

29509

South Asian (SAS)

AF:

0.0000196

AC:

AN:

50984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3791

European-Non Finnish (NFE)

AF:

0.000158

AC:

112

AN:

708141

Other (OTH)

AF:

0.0000728

AC:

AN:

41189

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000799

AC:

AN:

112693

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34855

show subpopulations

African (AFR)

AF:

0.0000644

AC:

AN:

31062

American (AMR)

AF:

0.00

AC:

AN:

10666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.000278

AC:

AN:

3600

South Asian (SAS)

AF:

0.000363

AC:

AN:

2757

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000937

AC:

AN:

53365

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.92

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.27

FATHMM_MKL

Benign

0.00037

LIST_S2

Benign

0.42

M_CAP

Benign

0.038

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.12

PhyloP100

0.011

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.54

REVEL

Benign

0.21

Sift

Benign

0.31

Sift4G

Benign

0.45

Polyphen

0.0040

Vest4

0.033

MVP

0.085

MPC

0.29

ClinPred

0.018

GERP RS

-4.0

Varity_R

0.028

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over