LAT2

Chr 7

linker for activation of T cells family member 2

Also known as: HSPC046, LAB, NTAL, WBSCR15, WBSCR5, WSCR5

NCBI Gene: 7462 ENSG00000086730 UniProt: Q9GZY6 OMIM: 605719

LAT2 encodes a transmembrane adaptor protein that couples high-affinity immunoglobulin receptors (including IgE receptors in mast cells and IgG receptors in myeloid cells) with downstream signaling cascades through recruitment of GRB2. LAT2 is located in the 7q11.23 region commonly deleted in Williams syndrome, a multisystem developmental disorder affecting cardiovascular, neurodevelopmental, and other organ systems. The gene shows low constraint against loss-of-function variants (pLI 0.0002), and inheritance follows an autosomal dominant pattern when considering Williams syndrome deletions.

OMIM ResearchSummary from RefSeq, UniProt

This gene is one of the contiguous genes at 7q11.23 commonly deleted in Williams syndrome, a multisystem developmental disorder. This gene consists of at least 14 exons, and its alternative splicing generates 3 transcript variants, all encoding the same protein. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— LAT2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

33 VUS of 57 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?

0.83LOEUF

pLI 0.000

Z-score 2.09

OE 0.48 (0.29–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.02Z-score

OE missense 1.01 (0.88–1.15)

145 obs / 144.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.83)

0≤0.351.4

Missense OE?1.01 (0.88–1.15)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 9 / 18.8Missense obs/exp: 145 / 144.2Syn Z: 1.39

This gene — mechanism propensity

0.7130th %ile

GOF

0.72top 25%

LOF

0.2288th %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

57 submitted variants in ClinVar

ClinVar

Classification Summary

VUS33

Likely Benign7

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	33	33
Likely Benign	7	7
Benign	0	0
Total	40	40

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

View in ClinVar →

165 pathogenic / likely-pathogenic (of 172) ClinVar copy-number / structural variants overlap LAT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →