21-44920928-A-G

Variant names:

• chr21-44920928-A-G
• rs2070947
• ENST00000498666.5:n.33T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000498666.5(ITGB2):​n.33T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,340 control chromosomes in the GnomAD database, including 4,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4486 hom., cov: 32)
  • Exomes 𝑓: 0.22 (5 hom.)
• Consequence: ITGB2 ENST00000498666.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.321
• Publications: 18 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-AS1 (HGNC:44304): (ITGB2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-44920928-A-G is Benign according to our data. Variant chr21-44920928-A-G is described in ClinVar as Benign. ClinVar VariationId is 340189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5	c.-111T>C		upstream_gene_variant		ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1	c.-111T>C		upstream_gene_variant			NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33283 AN: 152016 Hom.: 4489 Cov.: 32

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.218 AC: 45 AN: 206 Hom.: 5 Cov.: 0 AF XY: 0.224 AC XY: 38 AN XY: 170

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.125 AC: 1 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.233 AC: 41 AN: 176

Other (OTH) AF: 0.167 AC: 2 AN: 12

GnomAD4 genome AF: 0.219 AC: 33278 AN: 152134 Hom.: 4486 Cov.: 32 AF XY: 0.212 AC XY: 15788 AN XY: 74378

African (AFR) AF: 0.0636 AC: 2640 AN: 41530

American (AMR) AF: 0.260 AC: 3980 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3472

East Asian (EAS) AF: 0.217 AC: 1121 AN: 5164

South Asian (SAS) AF: 0.154 AC: 741 AN: 4812

European-Finnish (FIN) AF: 0.218 AC: 2313 AN: 10594

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20705 AN: 67960

Other (OTH) AF: 0.266 AC: 563 AN: 2114

Alfa AF: 0.283 Hom.: 14019

Bravo AF: 0.218

Asia WGS AF: 0.183 AC: 637 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Leukocyte adhesion deficiency 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.6
DANN	Benign	0.37
PhyloP100		0.32
PromoterAI		-0.13	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2070947; hg19: chr21-46340843; COSMIC: COSV105127942; COSMIC: COSV105127942;