rs5030672

Positions:

chr21-44889397-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_ModerateBP4_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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PS1

Transcript NM_000211.5 (ITGB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

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 [Likely_benign]. Clinvar id is 9463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44889397-G-A is described in Lovd as [Likely_benign]. Variant chr21-44889397-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1 link	c.1756C>T	p.Arg586Trp	missense_variant	13/16		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

GnomAD3 exomes

AF:

0.00859

AC:

2124

AN:

247144

Hom.:

AF XY:

0.00879

AC XY:

1181

AN XY:

134374

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 SAS exome

AF:

0.000885

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

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00175

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000870

Gnomad4 FIN exome

AF:

0.0489

Gnomad4 NFE exome

AF:

0.00827

Gnomad4 OTH exome

AF:

0.00676

GnomAD4 genome

AF:

0.00791

AC:

1204

AN:

152250

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

772

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0596

Gnomad4 NFE

AF:

0.00676

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00552

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	ITGB2: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 22134107, 22995991, 20981092, 1346613, 28600779) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Leukocyte adhesion deficiency 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

ITGB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2020

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over