21-44888885-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000211.5(ITGB2):c.1888G>A(p.Glu630Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,605,294 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 8 hom., cov: 34)

Exomes 𝑓: 0.0065 ( 50 hom. )

Consequence

ITGB2
NM_000211.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.85

Publications

18 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018218666).

BP6

Variant 21-44888885-C-T is Benign according to our data. Variant chr21-44888885-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445547.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 = 0.00508 (773/152280) while in subpopulation NFE AF = 0.00644 (438/68014). AF 95% confidence interval is 0.00594. There are 8 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5 link	c.1888G>A	p.Glu630Lys	missense_variant	Exon 14 of 16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1 link	c.1888G>A	p.Glu630Lys	missense_variant	Exon 14 of 16		NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes

AF:

0.00508

AC:

773

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00644

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00496

AC:

1200

AN:

241732

AF XY:

0.00491

show subpopulations

Gnomad AFR exome

AF:

0.000900

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.000502

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.00697

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00646

AC:

9381

AN:

1453014

Hom.:

Cov.:

AF XY:

0.00635

AC XY:

4589

AN XY:

723150

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33470

American (AMR)

AF:

0.00136

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0183

AC:

821

AN:

44896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00735

AC:

8171

AN:

1111818

Other (OTH)

AF:

0.00459

AC:

277

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

506

1011

1517

2022

2528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.00508

AC:

773

AN:

152280

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

431

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41564

American (AMR)

AF:

0.00294

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0213

AC:

226

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00644

AC:

438

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

130

173

216

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:

0.00544

Hom.:

Bravo

AF:

0.00380

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00515

AC:

624

EpiCase

AF:

0.00627

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukocyte adhesion deficiency 1

Benign:4

Jan 13, 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in the literature in at least 10 individuals with chronic lymphocytic leukemia (CLL) (Goldin 2016 PMID:27629550, Blackburn 2017 PMID:28490671); however at least 1 study did not identify an enrichment of the variant in cases vs. controls. This variant was also identified in 3 individuals with congenital heart defects (Russell 2019 PMID:31453292). This variant is present in the Genome Aggregation Database (Highest reported MAF 2.1% (226/10616) including 8 homozygotes (https://gnomad.broadinstitute.org/variant/21-44888885-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with multiple labs classifying this variant as Benign or Likely Benign (Variation ID:445547). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITGB2: BS2 -

Jun 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

.;.;T;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.81

.;.;T;.;.;T

MetaRNN

Benign

0.018

T;T;T;T;T;T

MetaSVM

Uncertain

0.51

PhyloP100

1.9

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.5

N;N;D;N;N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.017

D;D;D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D;D;D

Vest4

0.82

MVP

0.90

MPC

1.1

ClinPred

0.056

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.67

Mutation Taster

=61/39

polymorphism

(source)

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

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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