rs769571214

Variant names:

• chr21-44901608-T-G
• rs769571214
• NM_000211.5:c.625A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000211.5(ITGB2):​c.625A>C​(p.Lys209Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.41

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a domain VWFA (size 239) in uniprot entity ITB2_HUMAN there are 70 pathogenic changes around while only 5 benign (93%) in NM_000211.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5	c.625A>C	p.Lys209Gln	missense_variant	Exon 6 of 16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1	c.625A>C	p.Lys209Gln	missense_variant	Exon 6 of 16		NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251476 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000129 AC XY: 94 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597 AC: 2 AN: 33480

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.000201 AC: 224 AN: 1112010

Gnomad4 Remaining exome AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000941 AC XY: 7 AN XY: 74370

Gnomad4 AFR AF: 0.0000482 AC: 0.0000482416 AN: 0.0000482416

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000191 AC: 0.000191047 AN: 0.000191047

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Mar 18, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leukocyte adhesion deficiency 1 Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 209 of the ITGB2 protein (p.Lys209Gln). This variant is present in population databases (rs769571214, gnomAD 0.01%). 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: 530683). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	Benign	0.10
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	.;.;T;.;.;.;.
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	.;.;T;.;.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.044	D;D;T;D;D;D;D
Sift4G	Benign	0.19	T;T;T;T;T;T;T
Vest4		0.37
MutPred		0.68		Loss of methylation at K209 (P = 0.0332);Loss of methylation at K209 (P = 0.0332);.;Loss of methylation at K209 (P = 0.0332);Loss of methylation at K209 (P = 0.0332);Loss of methylation at K209 (P = 0.0332);.;
MVP		0.94
MPC		0.45
ClinPred		0.10	T
GERP RS		4.3
gMVP		0.67
Mutation Taster		=67/33	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

Publications

LitVar

Other links and lift over

dbSNP: rs769571214; hg19: chr21-46321523;