21-44901646-T-G

Variant names:

• chr21-44901646-T-G
• rs137852610
• NM_000211.5:c.587A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000211.5(ITGB2):​c.587A>C​(p.Lys196Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.04
• Publications: 6 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain VWFA (size 239) in uniprot entity ITB2_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 21-44901646-T-G is Pathogenic according to our data. Variant chr21-44901646-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9459.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000211.5. 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.587A>C	p.Lys196Thr	missense	Exon 6 of 16	NP_000202.3
	ITGB2	NM_001127491.3		c.587A>C	p.Lys196Thr	missense	Exon 6 of 16	NP_001120963.2
	ITGB2	NM_001303238.2		c.380A>C	p.Lys127Thr	missense	Exon 6 of 16	NP_001290167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB2	ENST00000652462.1	MANE Select	c.587A>C	p.Lys196Thr	missense	Exon 6 of 16	ENSP00000498780.1
	ITGB2	ENST00000302347.10	TSL:1	c.587A>C	p.Lys196Thr	missense	Exon 6 of 17	ENSP00000303242.6
	ITGB2	ENST00000397852.5	TSL:1	c.587A>C	p.Lys196Thr	missense	Exon 5 of 15	ENSP00000380950.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Leukocyte adhesion deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.55	T
PhyloP100		1.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Vest4		0.23
MutPred		0.76		Loss of methylation at K196 (P = 0.0042)
MVP		0.84
MPC		0.39
ClinPred		0.082	T
GERP RS		0.12
gMVP		0.61
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137852610; hg19: chr21-46321561;