21-44907014-C-T

Variant names:

• chr21-44907014-C-T
• rs141799330
• NM_000211.5:c.229G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000211.5(ITGB2):​c.229G>A​(p.Asp77Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,614,086 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D77Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.51
• Publications: 6 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 (MetaRNN=0.012335122).
• BP6: Variant 21-44907014-C-T is Benign according to our data. Variant chr21-44907014-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00291 (443/152264) while in subpopulation AFR AF = 0.00987 (410/41554). AF 95% confidence interval is 0.00908. There are 2 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	NM_000211.5	MANE Select	c.229G>A	p.Asp77Asn	missense	Exon 4 of 16	NP_000202.3
	ITGB2	NM_001127491.3		c.229G>A	p.Asp77Asn	missense	Exon 4 of 16	NP_001120963.2
	ITGB2	NM_001303238.2		c.22G>A	p.Asp8Asn	missense	Exon 4 of 16	NP_001290167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	ENST00000652462.1	MANE Select	c.229G>A	p.Asp77Asn	missense	Exon 4 of 16	ENSP00000498780.1
	ITGB2	ENST00000302347.10	TSL:1	c.229G>A	p.Asp77Asn	missense	Exon 4 of 17	ENSP00000303242.6
	ITGB2	ENST00000397852.5	TSL:1	c.229G>A	p.Asp77Asn	missense	Exon 3 of 15	ENSP00000380950.1

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 444 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000776 AC: 195 AN: 251426 AF XY: 0.000530

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000364 AC: 532 AN: 1461822 Hom.: 2 Cov.: 32 AF XY: 0.000309 AC XY: 225 AN XY: 727208

African (AFR) AF: 0.0117 AC: 392 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111962

Other (OTH) AF: 0.000762 AC: 46 AN: 60394

GnomAD4 genome AF: 0.00291 AC: 443 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74418

African (AFR) AF: 0.00987 AC: 410 AN: 41554

American (AMR) AF: 0.00150 AC: 23 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.00358

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 1 Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

not specified Benign:1

Feb 26, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.30	T
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.077	T
Sift4G	Benign	0.39	T
Vest4		0.37
MVP		0.88
MPC		0.35
ClinPred		0.0041	T
GERP RS		2.8
gMVP		0.54
Mutation Taster		=97/3	polymorphism

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: rs141799330; hg19: chr21-46326929; COSMIC: COSV105127966; COSMIC: COSV105127966;