Genetic Variant ITGB2:p.Glu576* (chr21-44889427-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000211.5(ITGB2):c.1726G>T(p.Glu576*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ITGB2
NM_000211.5 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.98

Publications

0 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ITGB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000211.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITGB2	NM_000211.5	MANE Select	c.1726G>T	p.Glu576*	stop_gained	Exon 13 of 16	NP_000202.3	P05107
ITGB2	NM_001127491.3		c.1726G>T	p.Glu576*	stop_gained	Exon 13 of 16	NP_001120963.2	P05107
ITGB2	NM_001303238.2		c.1519G>T	p.Glu507*	stop_gained	Exon 13 of 16	NP_001290167.1	B4E0R1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITGB2	ENST00000652462.1	MANE Select	c.1726G>T	p.Glu576*	stop_gained	Exon 13 of 16	ENSP00000498780.1	A0A494C0X7
ITGB2	ENST00000302347.10	TSL:1	c.1798G>T	p.Glu600*	stop_gained	Exon 14 of 17	ENSP00000303242.6	A0AAA9WZN5
ITGB2	ENST00000397852.5	TSL:1	c.1726G>T	p.Glu576*	stop_gained	Exon 12 of 15	ENSP00000380950.1	P05107

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39466

South Asian (SAS)

AF:

0.00

AC:

AN:

85670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110320

Other (OTH)

AF:

0.00

AC:

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Benign

0.92

Eigen

Benign

-0.55

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.050

PhyloP100

-2.0

Vest4

0.88

GERP RS

-9.8

Mutation Taster

=3/197

disease causing (fs/PTC)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over