21-44886246-C-T

Variant names:

• chr21-44886246-C-T
• rs684
• ENST00000498666.5:n.4488G>A

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.4488G>A 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 0.204 in 1,002,834 control chromosomes in the GnomAD database, including 22,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3090 hom., cov: 31)
  • Exomes 𝑓: 0.21 (19091 hom.)
• Consequence: ITGB2 ENST00000498666.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.420
• Publications: 19 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, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-44886246-C-T is Benign according to our data. Variant chr21-44886246-C-T is described in ClinVar as Benign. ClinVar VariationId is 340134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5	c.*122G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1	c.*122G>A		3_prime_UTR_variant	Exon 16 of 16		NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29765 AN: 151796 Hom.: 3085 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0840

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.206 AC: 175103 AN: 850920 Hom.: 19091 Cov.: 11 AF XY: 0.208 AC XY: 92222 AN XY: 444294

African (AFR) AF: 0.160 AC: 3492 AN: 21808

American (AMR) AF: 0.128 AC: 5336 AN: 41752

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 5446 AN: 21940

East Asian (EAS) AF: 0.0923 AC: 3356 AN: 36346

South Asian (SAS) AF: 0.195 AC: 14191 AN: 72950

European-Finnish (FIN) AF: 0.164 AC: 8345 AN: 50758

Middle Eastern (MID) AF: 0.302 AC: 950 AN: 3144

European-Non Finnish (NFE) AF: 0.223 AC: 125541 AN: 562274

Other (OTH) AF: 0.211 AC: 8446 AN: 39948

GnomAD4 genome AF: 0.196 AC: 29778 AN: 151914 Hom.: 3090 Cov.: 31 AF XY: 0.192 AC XY: 14260 AN XY: 74230

African (AFR) AF: 0.162 AC: 6701 AN: 41418

American (AMR) AF: 0.189 AC: 2880 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3472

East Asian (EAS) AF: 0.0840 AC: 433 AN: 5154

South Asian (SAS) AF: 0.189 AC: 909 AN: 4806

European-Finnish (FIN) AF: 0.161 AC: 1694 AN: 10554

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15592 AN: 67930

Other (OTH) AF: 0.223 AC: 471 AN: 2110

Alfa AF: 0.223 Hom.: 3030

Bravo AF: 0.195

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leukocyte adhesion deficiency 1 Benign:1

Jan 13, 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	-0.83
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs684; hg19: chr21-46306161; COSMIC: COSV56609304; COSMIC: COSV56609304;