rs745917556

Variant names:

• chr21-44903464-C-A
• rs745917556
• NM_000211.5:c.400G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-44903464-C-A
• chr21-44903464-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000211.5(ITGB2):​c.400G>T​(p.Asp134Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D134E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	NM_000211.5	MANE Select	c.400G>T	p.Asp134Tyr	missense	Exon 5 of 16	NP_000202.3	P05107
	ITGB2	NM_001127491.3		c.400G>T	p.Asp134Tyr	missense	Exon 5 of 16	NP_001120963.2	P05107
	ITGB2	NM_001303238.2		c.193G>T	p.Asp65Tyr	missense	Exon 5 of 16	NP_001290167.1	B4E0R1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	ENST00000652462.1	MANE Select	c.400G>T	p.Asp134Tyr	missense	Exon 5 of 16	ENSP00000498780.1	A0A494C0X7
	ITGB2	ENST00000302347.10	TSL:1	c.400G>T	p.Asp134Tyr	missense	Exon 5 of 17	ENSP00000303242.6	A0AAA9WZN5
	ITGB2	ENST00000397852.5	TSL:1	c.400G>T	p.Asp134Tyr	missense	Exon 4 of 15	ENSP00000380950.1	P05107

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leukocyte adhesion deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
PhyloP100		5.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.99
MutPred		0.97		Loss of phosphorylation at Y137 (P = 0.0749)
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
gMVP		0.96
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745917556; hg19: chr21-46323379;