21-44891898-A-G

Variant names:

• chr21-44891898-A-G
• rs235326
• NM_000211.5:c.1323T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000211.5(ITGB2):​c.1323T>C​(p.Val441Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,612,870 control chromosomes in the GnomAD database, including 375,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42687 hom., cov: 34)
  • Exomes 𝑓: 0.67 (332767 hom.)
• Consequence: ITGB2 NM_000211.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -2.01

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-44891898-A-G is Benign according to our data. Variant chr21-44891898-A-G is described in ClinVar as [Benign]. Clinvar id is 340155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44891898-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5	c.1323T>C	p.Val441Val	synonymous_variant	Exon 11 of 16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1	c.1323T>C	p.Val441Val	synonymous_variant	Exon 11 of 16		NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112334 AN: 152094 Hom.: 42620 Cov.: 34

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.739

GnomAD3 exomes AF: 0.681 AC: 170459 AN: 250414 Hom.: 58896 AF XY: 0.678 AC XY: 91841 AN XY: 135552

Gnomad AFR exome AF: 0.926

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.797

Gnomad SAS exome AF: 0.646

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.670

Gnomad OTH exome AF: 0.672

GnomAD4 exome AF: 0.673 AC: 982670 AN: 1460658 Hom.: 332767 Cov.: 62 AF XY: 0.671 AC XY: 487857 AN XY: 726650

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.592

Gnomad4 ASJ exome AF: 0.665

Gnomad4 EAS exome AF: 0.766

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.666

Gnomad4 OTH exome AF: 0.690

GnomAD4 genome AF: 0.739 AC: 112467 AN: 152212 Hom.: 42687 Cov.: 34 AF XY: 0.736 AC XY: 54785 AN XY: 74414

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.663

Gnomad4 EAS AF: 0.778

Gnomad4 SAS AF: 0.653

Gnomad4 FIN AF: 0.671

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.743

Alfa AF: 0.674 Hom.: 21940

Bravo AF: 0.747

Asia WGS AF: 0.738 AC: 2567 AN: 3478

EpiCase AF: 0.677

EpiControl AF: 0.683

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leukocyte adhesion deficiency 1 Benign:3

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs235326; hg19: chr21-46311813; COSMIC: COSV56608840; COSMIC: COSV56608840;