chr21-44907081-C-T

Position:

• chr21-44907081-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000211.5(ITGB2):​c.162G>A​(p.Pro54Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,603,324 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: ITGB2 NM_000211.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -4.12

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-44907081-C-T is Benign according to our data. Variant chr21-44907081-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340179.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr21-44907081-C-T is described in Lovd as [Likely_benign]. Variant chr21-44907081-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.002 (304/152274) while in subpopulation NFE AF= 0.0035 (238/68012). AF 95% confidence interval is 0.00313. There are 1 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB2	NM_000211.5	c.162G>A	p.Pro54Pro	synonymous_variant	4/16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1	c.162G>A	p.Pro54Pro	synonymous_variant	4/16		NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00172 AC: 424 AN: 246452 Hom.: 3 AF XY: 0.00174 AC XY: 231 AN XY: 133116

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.000844

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00304 AC: 4414 AN: 1451050 Hom.: 13 Cov.: 32 AF XY: 0.00292 AC XY: 2102 AN XY: 720052

Gnomad4 AFR exome AF: 0.000750

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.000557

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74452

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00199

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukocyte adhesion deficiency 1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.29

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: rs138303556; hg19: chr21-46326996;