CHP2

Chr 16

calcineurin like EF-hand protein 2

NCBI Gene: 63928 ENSG00000166869 UniProt: O43745

This protein functions as a calcium-binding cofactor that regulates cell pH by controlling plasma membrane Na+/H+ exchange activity and activates calcineurin phosphatase activity in the calcineurin/NFAT signaling pathway. Mutations in CHP2 cause autosomal recessive neurodevelopmental disorder with seizures and brain atrophy, typically presenting in early childhood. The gene shows minimal constraint against loss-of-function variants, which is consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, UniProt

This gene product is a small calcium-binding protein that regulates cell pH by controlling plasma membrane-type Na+/H+ exchange activity. This protein shares sequence similarity with calcineurin B and can bind to and stimulate the protein phosphatase activity of calcineurin A (CnA) and functions in the calcineurin/NFAT (nuclear factor of activated T cells) signaling pathway. Another member of the CHP subfamily, Calcineurin B homologous protein 1, is located on Chromosome 15 and is an inhibitor of calcineurin activity and has a genetic phenotype associated with Parkinson's Disease (OMIM:606988). This gene was initially identified as a tumor-associated antigen and was previously referred to as Hepatocellular carcinoma-associated antigen 520. [provided by RefSeq, Jul 2013]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.47

Clinical Summary— CHP2

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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

40 VUS of 44 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.47LOEUF

pLI 0.000

Z-score 0.42

OE 0.87 (0.53–1.47)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.68Z-score

OE missense 1.17 (1.02–1.34)

145 obs / 123.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.87 (0.53–1.47)

0≤0.351.4

Missense OE?1.17 (1.02–1.34)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 10 / 11.5Missense obs/exp: 145 / 123.8Syn Z: 0.47

This gene — mechanism propensity

0.7132th %ile

GOF

0.78top 25%

LOF

0.3163th %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

44 submitted variants in ClinVar

ClinVar

Classification Summary

VUS40

Likely Benign1

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	40	40
Likely Benign	1	1
Benign	0	0
Total	41	41

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap CHP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →