21-44886383-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000211.5(ITGB2):c.2295G>C(p.Lys765Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0420

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23674843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.2295G>C	p.Lys765Asn	missense_variant	16/16	ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.2295G>C	p.Lys765Asn	missense_variant	16/16		NM_000211.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251468 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.2295G>C (p.K765N) alteration is located in exon 16 (coding exon 15) of the ITGB2 gene. This alteration results from a G to C substitution at nucleotide position 2295, causing the lysine (K) at amino acid position 765 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Leukocyte adhesion deficiency 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2022

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 765 of the ITGB2 protein (p.Lys765Asn). This variant is present in population databases (rs750477817, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with ITGB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 936550). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.74	N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T
Vest4		0.051
MutPred		0.44		Loss of methylation at K765 (P = 0.0016);Loss of methylation at K765 (P = 0.0016);.;Loss of methylation at K765 (P = 0.0016);Loss of methylation at K765 (P = 0.0016);Loss of methylation at K765 (P = 0.0016);
MVP		0.88
MPC		0.49
ClinPred		0.097	T
GERP RS		4.8
gMVP		0.63

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: rs750477817; hg19: chr21-46306298;