rs483352814

chr21-44901527-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000211.5(ITGB2):c.706G>A(p.Gly236Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G236W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.71

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 9) in uniprot entity ITB2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44901527-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 21-44901527-C-T is Pathogenic according to our data. Variant chr21-44901527-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100759.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-44901527-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.706G>A	p.Gly236Arg	missense_variant	6/16	ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.706G>A	p.Gly236Arg	missense_variant	6/16		NM_000211.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251180 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leukocyte adhesion deficiency 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Genomic Research Center, Shahid Beheshti University of Medical Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.025	D;D;D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D
Vest4		0.94
MutPred		0.92		Gain of methylation at G236 (P = 0.0287);Gain of methylation at G236 (P = 0.0287);.;Gain of methylation at G236 (P = 0.0287);Gain of methylation at G236 (P = 0.0287);Gain of methylation at G236 (P = 0.0287);.;
MVP		0.96
MPC		1.1
ClinPred		0.97	D
GERP RS		4.2
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs483352814; hg19: chr21-46321442;