chr21-44903482-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000211.5(ITGB2):c.382G>A(p.Asp128Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D128Y) has been classified as Pathogenic.
Frequency
Consequence
NM_000211.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGB2 | NM_000211.5 | c.382G>A | p.Asp128Asn | missense_variant | 5/16 | ENST00000652462.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB2 | ENST00000652462.1 | c.382G>A | p.Asp128Asn | missense_variant | 5/16 | NM_000211.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251400Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727218
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Leukocyte adhesion deficiency 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 1992 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp128 amino acid residue in ITGB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20549317, 25514840, 28445705, 32279896). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGB2 protein function. ClinVar contains an entry for this variant (Variation ID: 9467). This missense change has been observed in individual(s) with leukocyte adhesion deficiency (PMID: 1590804, 24338230, 26497373; Invitae). This variant is present in population databases (rs137852615, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 128 of the ITGB2 protein (p.Asp128Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at