chr21-44889397-G-A

Variant names:

• chr21-44889397-G-A
• rs5030672
• NM_000211.5:c.1756C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R586Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (105 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.735
• Publications: 20 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000211.5
• 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 Benign/Likely_benign. ClinVar VariationId is 9463.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 = 0.00791 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.1756C>T	p.Arg586Trp	missense	Exon 13 of 16	NP_000202.3	P05107
	ITGB2	NM_001127491.3		c.1756C>T	p.Arg586Trp	missense	Exon 13 of 16	NP_001120963.2	P05107
	ITGB2	NM_001303238.2		c.1549C>T	p.Arg517Trp	missense	Exon 13 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.1756C>T	p.Arg586Trp	missense	Exon 13 of 16	ENSP00000498780.1	A0A494C0X7
	ITGB2	ENST00000302347.10	TSL:1	c.1828C>T	p.Arg610Trp	missense	Exon 14 of 17	ENSP00000303242.6	A0AAA9WZN5
	ITGB2	ENST00000397852.5	TSL:1	c.1756C>T	p.Arg586Trp	missense	Exon 12 of 15	ENSP00000380950.1	P05107

Frequencies

GnomAD3 genomes AF: 0.00793 AC: 1206 AN: 152134 Hom.: 23 Cov.: 33

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

GnomAD2 exomes AF: 0.00859 AC: 2124 AN: 247144 AF XY: 0.00879

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 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.: 33 AF XY: 0.00829 AC XY: 6024 AN XY: 726508

African (AFR) AF: 0.00128 AC: 43 AN: 33470

American (AMR) AF: 0.00175 AC: 78 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86182

European-Finnish (FIN) AF: 0.0489 AC: 2559 AN: 52354

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00827 AC: 9191 AN: 1111732

Other (OTH) AF: 0.00676 AC: 408 AN: 60348

GnomAD4 genome AF: 0.00791 AC: 1204 AN: 152250 Hom.: 23 Cov.: 33 AF XY: 0.0104 AC XY: 772 AN XY: 74444

African (AFR) AF: 0.00140 AC: 58 AN: 41550

American (AMR) AF: 0.00248 AC: 38 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0596 AC: 632 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00676 AC: 460 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00569 Hom.: 10

Bravo AF: 0.00390

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00755 AC: 915

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Leukocyte adhesion deficiency 1 (3)
-	-	1	ITGB2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.056	T
MetaSVM	Uncertain	-0.059	T
PhyloP100		-0.73
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Vest4		0.72
MVP		0.82
MPC		0.34
ClinPred		0.061	T
GERP RS		-9.8
gMVP		0.48
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5030672; hg19: chr21-46309312; COSMIC: COSV56609809; COSMIC: COSV56609809;