rs138659490

Positions:

• chr21-44891863-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000211.5(ITGB2):​c.1358G>A​(p.Ser453Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00065 in 1,611,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.939

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest Cysteine-rich tandem repeats (size 168) in uniprot entity ITB2_HUMAN there are 18 pathogenic changes around while only 5 benign (78%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029739767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.1358G>A	p.Ser453Asn	missense_variant	11/16	ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.1358G>A	p.Ser453Asn	missense_variant	11/16		NM_000211.5	P1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000533 AC: 133 AN: 249544 Hom.: 0 AF XY: 0.000577 AC XY: 78 AN XY: 135180

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000876

Gnomad NFE exome AF: 0.000787

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000663 AC: 967 AN: 1459520 Hom.: 0 Cov.: 30 AF XY: 0.000628 AC XY: 456 AN XY: 726148

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000821

Gnomad4 NFE exome AF: 0.000783

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74380

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000382

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 453 of the ITGB2 protein (p.Ser453Asn). This variant is present in population databases (rs138659490, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with leukocyte adhesion deficiency (PMID: 22134107). ClinVar contains an entry for this variant (Variation ID: 530681). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect ITGB2 function (PMID: 25514840). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.2
DANN	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.030	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.70	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.42	T;T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T
Vest4		0.14
MVP		0.81
MPC		0.31
ClinPred		0.0027	T
GERP RS		0.55
gMVP		0.69

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: rs138659490; hg19: chr21-46311778;