NHERF2

Chr 16AD

NHERF family PDZ scaffold protein 2

Also known as: E3KARP, NHE3RF2, NHERF-2, OCTS2, SIP-1, SIP1, SLC9A3R2, TKA-1

NCBI Gene: 9351 ENSG00000065054 UniProt: Q15599 OMIM: 606553

This gene encodes a PDZ scaffolding protein that connects plasma membrane proteins to the actin cytoskeleton and regulates their surface expression, including the sodium/hydrogen exchanger 3 and the cystic fibrosis transmembrane regulator ion channel. Mutations cause autosomal dominant deafness (DFNA82). The gene shows tolerance to loss-of-function variants with a low pLI score.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the NHERF family of PDZ scaffolding proteins. These proteins mediate many cellular processes by binding to and regulating the membrane expression and protein-protein interactions of membrane receptors and transport proteins. The encoded protein plays a role in intestinal sodium absorption by regulating the activity of the sodium/hydrogen exchanger 3, and may also regulate the cystic fibrosis transmembrane regulator (CFTR) ion channel. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.702 OMIM phenotypes

Clinical Summary— NHERF2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 90 VUS of 104 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?

0.70LOEUF

pLI 0.038

Z-score 2.39

OE 0.33 (0.17–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.17Z-score

OE missense 1.03 (0.92–1.16)

209 obs / 202.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.33 (0.17–0.70)

0≤0.351.4

Missense OE?1.03 (0.92–1.16)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 5 / 15.0Missense obs/exp: 209 / 202.1Syn Z: -0.95

This gene — mechanism propensity

0.6841th %ile

GOF

0.81top 10%

LOF

0.3259th %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

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS90

Likely Benign6

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	88	0	2	90
Likely Benign	4	1	1	6
Benign	2	0	0	2
Total	94	2	3	99

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 62) ClinVar copy-number / structural variants overlap NHERF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →