21-44907081-C-T

Variant names:

• chr21-44907081-C-T
• rs138303556
• NM_000211.5:c.162G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000652462.1(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 ENST00000652462.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -4.12
• Publications: 2 publications found

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]

ITGB2 Gene-Disease associations (from GenCC):

• leukocyte adhesion deficiency 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 340179.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000652462.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	NM_000211.5	MANE Select	c.162G>A	p.Pro54Pro	synonymous	Exon 4 of 16	NP_000202.3
	ITGB2	NM_001127491.3		c.162G>A	p.Pro54Pro	synonymous	Exon 4 of 16	NP_001120963.2
	ITGB2	NM_001303238.2		c.-46G>A		5_prime_UTR	Exon 4 of 16	NP_001290167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	ENST00000652462.1	MANE Select	c.162G>A	p.Pro54Pro	synonymous	Exon 4 of 16	ENSP00000498780.1
	ITGB2	ENST00000302347.10	TSL:1	c.162G>A	p.Pro54Pro	synonymous	Exon 4 of 17	ENSP00000303242.6
	ITGB2	ENST00000397852.5	TSL:1	c.162G>A	p.Pro54Pro	synonymous	Exon 3 of 15	ENSP00000380950.1

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

GnomAD2 exomes AF: 0.00172 AC: 424 AN: 246452 AF XY: 0.00174

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 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

African (AFR) AF: 0.000750 AC: 25 AN: 33318

American (AMR) AF: 0.00119 AC: 53 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 108 AN: 25682

East Asian (EAS) AF: 0.000557 AC: 22 AN: 39486

South Asian (SAS) AF: 0.00191 AC: 163 AN: 85520

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52840

Middle Eastern (MID) AF: 0.000377 AC: 2 AN: 5306

European-Non Finnish (NFE) AF: 0.00349 AC: 3856 AN: 1104570

Other (OTH) AF: 0.00306 AC: 183 AN: 59886

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

African (AFR) AF: 0.000578 AC: 24 AN: 41552

American (AMR) AF: 0.00144 AC: 22 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00199

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Leukocyte adhesion deficiency 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.29
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138303556; hg19: chr21-46326996;