rs375743879

Variant names:

• chr21-44890230-C-T
• rs375743879
• NM_000211.5:c.1413-8G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000211.5(ITGB2):​c.1413-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,612,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: ITGB2 NM_000211.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006984
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -4.14
• Publications: 0 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-44890230-C-T is Benign according to our data. Variant chr21-44890230-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340153.

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.1413-8G>A		splice_region intron	N/A	NP_000202.3	P05107
	ITGB2	NM_001127491.3		c.1413-8G>A		splice_region intron	N/A	NP_001120963.2	P05107
	ITGB2	NM_001303238.2		c.1206-8G>A		splice_region intron	N/A	NP_001290167.1	B4E0R1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	ENST00000652462.1	MANE Select	c.1413-8G>A		splice_region intron	N/A	ENSP00000498780.1	A0A494C0X7
	ITGB2	ENST00000302347.10	TSL:1	c.1485-8G>A		splice_region intron	N/A	ENSP00000303242.6	A0AAA9WZN5
	ITGB2	ENST00000397852.5	TSL:1	c.1413-8G>A		splice_region intron	N/A	ENSP00000380950.1	P05107

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000589 AC: 147 AN: 249562 AF XY: 0.000643

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000589 AC: 860 AN: 1460680 Hom.: 0 Cov.: 33 AF XY: 0.000577 AC XY: 419 AN XY: 726672

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000230 AC: 12 AN: 52258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000711 AC: 791 AN: 1111982

Other (OTH) AF: 0.000629 AC: 38 AN: 60382

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74442

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000626 Hom.: 0

Bravo AF: 0.000480

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Leukocyte adhesion deficiency 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.15
DANN	Benign	0.47
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.022
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

Other links and lift over

dbSNP: rs375743879; hg19: chr21-46310145;