SH2D1B

Chr 1

SH2 domain containing 1B

Also known as: EAT2

NCBI Gene: 117157 ENSG00000198574 UniProt: O14796 OMIM: 608510

EAT2 is a cytoplasmic adapter protein that regulates signaling through SLAM family receptors on immune cells, particularly controlling natural killer cell function and dendritic cell responses. Mutations cause familial hemophagocytic lymphohistiocytosis type 4, an autosomal recessive disorder characterized by uncontrolled immune activation that typically presents in infancy or early childhood. The condition involves multiple organ systems including the hematopoietic, hepatic, and central nervous systems.

OMIM ResearchSummary from RefSeq, UniProt

By binding phosphotyrosines through its free SRC (MIM 190090) homology-2 (SH2) domain, EAT2 regulates signal transduction through receptors expressed on the surface of antigen-presenting cells (Morra et al., 2001 [PubMed 11689425]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.15

Clinical Summary— SH2D1B

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 VUS of 20 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.013

Z-score 1.30

OE 0.50 (0.25–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.32Z-score

OE missense 0.89 (0.73–1.10)

63 obs / 70.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.25–1.15)

0≤0.351.4

Missense OE?0.89 (0.73–1.10)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 4 / 8.0Missense obs/exp: 63 / 70.5Syn Z: -0.39

This gene — mechanism propensity

0.7326th %ile

GOF

0.76top 25%

LOF

0.2483th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

20 submitted variants in ClinVar

ClinVar

Classification Summary

VUS17

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	17	17
Likely Benign	0	0
Benign	0	0
Total	17	17

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SH2D1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →