rs5030670

chr21-44900488-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000211.5(ITGB2):c.742-13G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,112 control chromosomes in the GnomAD database, including 18,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1291 hom., cov: 33)
  • Exomes 𝑓: 0.15 (16940 hom.)
• Consequence: ITGB2 NM_000211.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.84

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-44900488-C-T is Benign according to our data. Variant chr21-44900488-C-T is described in ClinVar as [Benign]. Clinvar id is 100760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44900488-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.742-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.742-13G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000211.5	P1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18424 AN: 152084 Hom.: 1291 Cov.: 33

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.124 AC: 31148 AN: 250310 Hom.: 2338 AF XY: 0.128 AC XY: 17326 AN XY: 135492

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.0692

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.0302

Gnomad SAS exome AF: 0.0957

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.148 AC: 215805 AN: 1460910 Hom.: 16940 Cov.: 35 AF XY: 0.147 AC XY: 106668 AN XY: 726742

Gnomad4 AFR exome AF: 0.0589

Gnomad4 AMR exome AF: 0.0723

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.0228

Gnomad4 SAS exome AF: 0.0954

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.121 AC: 18419 AN: 152202 Hom.: 1291 Cov.: 33 AF XY: 0.120 AC XY: 8914 AN XY: 74408

Gnomad4 AFR AF: 0.0643

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.0999

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.140

Alfa AF: 0.137 Hom.: 441

Bravo AF: 0.113

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 1 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
not provided, no classification provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.11
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs5030670; hg19: chr21-46320403; COSMIC: COSV56610895; COSMIC: COSV56610895;