Genetic Variant IL1RAPL2:p.Ala106Val (chrX-105195709-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_017416.2(IL1RAPL2):c.317C>T(p.Ala106Val) variant causes a missense change. The variant allele was found at a frequency of 0.00262 in 1,210,206 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,006 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 36 hem., cov: 23)

Exomes 𝑓: 0.0027 ( 5 hom. 970 hem. )

Consequence

IL1RAPL2
NM_017416.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.60

Publications

6 publications found

Variant links:

Genes affected

IL1RAPL2 (HGNC:5997): (interleukin 1 receptor accessory protein like 2) The protein encoded by this gene is a member of the interleukin 1 receptor family. This protein is similar to the interleukin 1 accessory proteins, and is most closely related to interleukin 1 receptor accessory protein-like 1 (IL1RAPL1). This gene and IL1RAPL1 are located at a region on chromosome X that is associated with X-linked non-syndromic cognitive disability. [provided by RefSeq, Jul 2008]

IL1RAPL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010100216).

BP6

Variant X-105195709-C-T is Benign according to our data. Variant chrX-105195709-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 726619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 36 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017416.2. 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
	IL1RAPL2	NM_017416.2	MANE Select	c.317C>T	p.Ala106Val	missense	Exon 3 of 11	NP_059112.1	Q9NP60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RAPL2	ENST00000372582.6	TSL:1 MANE Select	c.317C>T	p.Ala106Val	missense	Exon 3 of 11	ENSP00000361663.1	Q9NP60

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

163

AN:

112244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000518

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000377

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00248

Gnomad OTH

AF:

0.00398

GnomAD2 exomes

AF:

0.00117

AC:

215

AN:

183334

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00214

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.00225

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.00274

AC:

3012

AN:

1097904

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

970

AN XY:

363266

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

26397

American (AMR)

AF:

0.000256

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00196

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.0000740

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00340

AC:

2862

AN:

841823

Other (OTH)

AF:

0.00200

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00145

AC:

163

AN:

112302

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

34472

show subpopulations

African (AFR)

AF:

0.000517

AC:

AN:

30958

American (AMR)

AF:

0.000376

AC:

AN:

10625

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3549

South Asian (SAS)

AF:

0.00

AC:

AN:

2682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00248

AC:

132

AN:

53242

Other (OTH)

AF:

0.00393

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00226

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00658

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00342

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.00229

EpiControl

AF:

0.00130

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

3.6

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

REVEL

Benign

0.10

Sift

Benign

0.16

Sift4G

Benign

0.10

Polyphen

0.0060

Vest4

0.21

MVP

0.52

MPC

1.1

ClinPred

0.031

GERP RS

3.4

Varity_R

0.14

gMVP

0.83

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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