rs137852616

Positions:

chr21-44900367-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Very_Strong

The NM_000211.5(ITGB2):c.850G>A(p.Gly284Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ITGB2
NM_000211.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.47

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 Pathogenic. 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

PM1

In a disulfide_bond (size 40) in uniprot entity ITB2_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000211.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 21-44900367-C-T is Pathogenic according to our data. Variant chr21-44900367-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44900367-C-T is described in Lovd as [Pathogenic]. Variant chr21-44900367-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB2	NM_000211.5 linkuse as main transcript	c.850G>A	p.Gly284Ser	missense_variant	7/16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1 linkuse as main transcript	c.850G>A	p.Gly284Ser	missense_variant	7/16		NM_000211.5	ENSP00000498780	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251272

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000709

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukocyte adhesion deficiency 1

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 30, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ITGB2 c.850G>A (p.Gly284Ser) missense variant has been reported in four studies in which it is found in a total of seven individuals with leukocyte adhesion deficiency, including two in a homozygous state, four in a compound heterozygous state (including two siblings) and one in a heterozygous state, along with a total of five unaffected heterozygous family members (Back et al. 1993; Wright et al. 1995; Fathallah et al. 2001; Uzel et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Cell surface expression of leukocyte integrins (CD11/CD18) on COS-7 cells carrying the p.Gly284Ser variant was significantly reduced compared to wild type (Wright et al. 1995; Uzel et al. 2008). In addition, Uzel et al. (2008) demonstrated that the binding of COS-7 cells carrying the p.Gly284Ser variant to ICAM-1 ligand coated plates was negligible compared to wild type. Based on the evidence, the p.Gly284Ser variant is classified as pathogenic for leukocyte adhesion deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 284 of the ITGB2 protein (p.Gly284Ser). This variant is present in population databases (rs137852616, gnomAD 0.007%). This missense change has been observed in individual(s) with leukocyte adhesion deficiency (PMID: 7705401, 11703376, 12488604, 17875809, 25703682). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9469). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGB2 protein function. Experimental studies have shown that this missense change affects ITGB2 function (PMID: 7705401, 12488604, 17875809, 25514840). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2022

Published functional studies demonstrate a damaging effect: variant impairs protein expression (Guan et al., 2014; Uzel et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28492532, 17467977, 7686755, 7143170, 17875809, 30412664, 30919141, 25514840, 32888943, 10886250, 33365035, 12488604, 7705401, 26434744, 33391282) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

.;.;D;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;.;D;.;.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0040

D;D;D;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D;T

Vest4

0.83

MutPred

0.90

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;

MVP

0.95

MPC

0.99

ClinPred

0.93

GERP RS

4.9

gMVP

0.74

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

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