rs5030672

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000211.5(ITGB2):c.1756C>T(p.Arg586Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 1,612,570 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R586Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0079 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 105 hom. )

Consequence

ITGB2
NM_000211.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.735

Publications

20 publications found

Variant links:

Genes affected

ITGB2 (HGNC:6155): (integrin subunit beta 2) This gene encodes an integrin beta chain, which combines with multiple different alpha chains to form different integrin heterodimers. Integrins are integral cell-surface proteins that participate in cell adhesion as well as cell-surface mediated signalling. The encoded protein plays an important role in immune response and defects in this gene cause leukocyte adhesion deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ITGB2 Gene-Disease associations (from GenCC):

leukocyte adhesion deficiency 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ITGB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000211.5

BP4

Computational evidence support a benign effect (MetaRNN=0.055984765).

BP6

Variant 21-44889397-G-A is Benign according to our data. Variant chr21-44889397-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00791 (1204/152250) while in subpopulation NFE AF = 0.00676 (460/68000). AF 95% confidence interval is 0.00625. There are 23 homozygotes in GnomAd4. There are 772 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5 link	c.1756C>T	p.Arg586Trp	missense_variant	Exon 13 of 16	ENST00000652462.1	NP_000202.3	P05107A0A494C0X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1 link	c.1756C>T	p.Arg586Trp	missense_variant	Exon 13 of 16		NM_000211.5	ENSP00000498780.1		A0A494C0X7

Frequencies

GnomAD3 genomes

AF:

0.00793

AC:

1206

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0596

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00678

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00859

AC:

2124

AN:

247144

AF XY:

0.00879

show subpopulations

Gnomad AFR exome

AF:

0.00139

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.0534

Gnomad NFE exome

AF:

0.00762

Gnomad OTH exome

AF:

0.00780

GnomAD4 exome

AF:

0.00851

AC:

12428

AN:

1460320

Hom.:

105

Cov.:

AF XY:

0.00829

AC XY:

6024

AN XY:

726508

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33470

American (AMR)

AF:

0.00175

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.000870

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.0489

AC:

2559

AN:

52354

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00827

AC:

9191

AN:

1111732

Other (OTH)

AF:

0.00676

AC:

408

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

756

1512

2268

3024

3780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.00791

AC:

1204

AN:

152250

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

772

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41550

American (AMR)

AF:

0.00248

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0596

AC:

632

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00676

AC:

460

AN:

68000

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

188

251

314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00569

Hom.:

Bravo

AF:

0.00390

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00755

AC:

915

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22134107, 22995991, 20981092, 1346613, 28600779) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITGB2: BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Leukocyte adhesion deficiency 1

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

ITGB2-related disorder

Benign:1

Mar 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;.;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.26

.;.;T;.;.;T

MetaRNN

Benign

0.056

T;T;T;T;T;T

MetaSVM

Uncertain

-0.059

PhyloP100

-0.73

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D;D

Vest4

0.72

MVP

0.82

MPC

0.34

ClinPred

0.061

GERP RS

-9.8

gMVP

0.48

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over