21-44901646-T-G

Position:

• chr21-44901646-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate

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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• 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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_000211.5 (ITGB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a domain VWFA (size 239) in uniprot entity ITB2_HUMAN there are 70 pathogenic changes around while only 6 benign (92%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.587A>C	p.Lys196Thr	missense_variant	6/16	ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.587A>C	p.Lys196Thr	missense_variant	6/16		NM_000211.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leukocyte adhesion deficiency 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

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;.;.;T;T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.00052	A;A;A;A;A;A
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.13	T;T;T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T;T
Vest4		0.23
MutPred		0.76		Loss of methylation at K196 (P = 0.0042);Loss of methylation at K196 (P = 0.0042);.;Loss of methylation at K196 (P = 0.0042);Loss of methylation at K196 (P = 0.0042);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852610; hg19: chr21-46321561;