BLNK

protein-coding

B cell linker, the group of SH2 domain containing

Gene summary

This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

MANE transcript

NM_013314.4

Inheritance

AR, AD

ClinVar variants

P:15U:147B:98

Top phenotype

Agammaglobulinemia 4, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr10:96,189,171-96,271,587

External References & Databases

Ensembl (ENSG00000095585)

Transcript & Mutation Effects

hg38 • Region Span ~82.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

agammaglobulinemia 4, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013289

Submitter: ClinGen

The relationship between BLNK and Agammaglobulinemia 4, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of February, 2021. BLNK encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. Agammaglobulinemia is characterized by absence of circulating B cells and low or absent serum immunoglobulin levels (PMID: 10583958). BLNK was first reported in relation to autosomal recessive Agammaglobulinemia 4 in 1999 (Minegishi et al, PMID: 10583958). Variants reported in this gene thus far include missense, nonsense, frameshift and splice site variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (7.5 points): There have been 8 patients, including a sibling pair, from 6 publications, till date, reported with biallelic variants in BLNK (PMID: 10583958, 24582315, 30619340, 25893637, 32194234, 19302039). The mechanism of disease is expected to be biallelic loss of function. Summary of experimental data (4.5 points): This gene-disease association is supported by in-vitro functional assays and animal models. BLNK is expressed in B lymphocytes (PMID: 10583957). BLNK is involved in BCR activation and B cell differentiation (PMID: 9697839). BLNK defects lead to a block of B-cell differentiation from the pro-B cell to the pre-B cell stage and accumulation of immature B cells (PMID: 24582315). A targeted knock-out mouse model (PMID: 10583957) has been reported that recapitulates the B-cell defect. In summary, the evidence to support the gene-disease relationship of BLNK and Agammaglobulinemia 4 is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Antibody Immunodeficiency GCEP on March 16, 2021 (SOP Version 8).

agammaglobulinemia 4, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013289

Submitter: Ambry Genetics

autosomal agammaglobulinemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011096

Submitter: Orphanet

agammaglobulinemia 4, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013289

Submitter: LiferaOmics

ClinGen AR agammaglobulinemia 4 : Definitive approved by ClinGen on 03/16/2021. ClinGen evidence summary: case-level genetic evidence = 7.5 points based on 8 patients (incl. a sibling pair) from 6 publications (PMIDs: 10583958, 24582315, 30619340, 25893637, 32194234, 19302039); experimental evidence = 4.5 points supported by expression/functional role and animal model data (PMIDs: 10583957, 9697839, 24582315). Baseline overall ≥12 - Definitive. Our case: consanguineous parents; nonsense NM_013314.3:c.145C>T; p.(Arg49Ter) (predicted LoF, consistent with BLNK AR LoF mechanism, consangunity). Case-level points (AR predicted/proven null) = 1.0; segregation = 0 (no genotyped affected relatives provided); case-control = 0 Overall score: 12.0 (capped)

agammaglobulinemia 4, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013289

Submitter: Labcorp Genetics (formerly Invitae)

agammaglobulinemia 4, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013289

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Agammaglobulinemia 4, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals can have immunodeficiency (which can involve frequent and severe infections, including reports of lethal bacterial sepsis) related to agammaglobulinemia, and antiinfectious prophylaxis (IVIG has been reported to be beneficial) and early and aggressive treatment of infections may be beneficial

Refs: 10583958

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BLNK variants in ClinVar

5 Conditions Cataloged

Agammaglobulinemia 4, autosomal recessiveTotal: 332

Inborn genetic diseasesTotal: 45

not specifiedTotal: 43

not providedTotal: 38

BLNK-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013314.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	89 clinvar	2 clinvar	93
missense			139 clinvar	7 clinvar		146
nonsense	2 clinvar	3 clinvar				5
start loss						0
frameshift	4 clinvar	1 clinvar				5
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	6 clinvar			11
Total	7	8	147	96	2	260

Highest pathogenic variant AF is 0.0000041065064

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013314.4	RefSeq	NP_037446.1	17	MANE Select
ENST00000224337.10	Ensembl	ENSP00000224337.6	17	MANE Select
NM_001114094.2	RefSeq	NP_001107566.1	16	Standard
NM_001258440.2	RefSeq	NP_001245369.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
Osteoclast differentiation - Homo sapiens (human)
NF-kappa B signaling pathway - Homo sapiens (human)
B Cell Receptor Signaling Pathway

Biological Process

inflammatory response
humoral immune response
transmembrane receptor protein tyrosine kinase signaling pathway
positive regulation of signal transduction
B cell differentiation

Molecular Function

transmembrane receptor protein tyrosine kinase adaptor activity
SH3/SH2 adaptor activity
protein binding

Cellular Component

cytoplasm
cytosol
plasma membrane
cytoplasmic ribonucleoprotein granule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000224337
Coding exons: 17
Length: 79887
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.50	183	250	0.733	0.0000135	2953
Missense (PolyPhen)		33	65.732	0.50204		800
Synonymous	-0.178	98	95.8	1.02	0.00000622	869
Loss of Function	4.25	7	33.6	0.208	0.00000191	373

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0	0.0	absent
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development. Plays a role in the activation of ERK/EPHB2, MAP kinase p38 and JNK. Modulates AP1 activation. Important for the activation of NF-kappa-B and NFAT. Plays an important role in BCR-mediated PLCG1 and PLCG2 activation and Ca(2+) mobilization and is required for trafficking of the BCR to late endosomes. However, does not seem to be required for pre-BCR- mediated activation of MAP kinase and phosphatidyl-inositol 3 (PI3) kinase signaling. May be required for the RAC1-JNK pathway. Plays a critical role in orchestrating the pro-B cell to pre-B cell transition. May play an important role in BCR-induced B-cell apoptosis. {ECO:0000269|PubMed:10583958, ECO:0000269|PubMed:15270728, ECO:0000269|PubMed:16912232, ECO:0000269|PubMed:9697839}.;
Disease: DISEASE: Agammaglobulinemia 4, autosomal recessive (AGM4) [MIM:613502]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. {ECO:0000269|PubMed:10583958}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.284

Intolerance Scores

LoFtool: 0.0565
RVIS EVS: -0.38
RVIS percentile EVS: 27.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.484

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium