WHRN

Chr 9AR

whirlin

Also known as: CIP98, DFNB31, PDZD7B, USH2D, WI

NCBI Gene: 25861 ENSG00000095397 UniProt: Q9P202 OMIM: 607928

The protein is essential for stereocilia elongation and maintenance in inner ear hair cells and for maintaining the periciliary membrane complex in retinal photoreceptors. Mutations cause autosomal recessive nonsyndromic hearing loss (DFNB31) or Usher syndrome type 2D, which combines hearing loss with progressive vision loss due to retinitis pigmentosa. The gene is highly intolerant to loss-of-function variants (LOEUF 0.668), reflecting its critical role in sensory organ development and maintenance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.672 OMIM phenotypes

Clinical Summary— WHRN

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Gene-Disease Validity (ClinGen)

Usher syndrome type 2D · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

57 unique Pathogenic / Likely Pathogenic· 443 VUS of 956 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — WHRN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.000

Z-score 2.94

OE 0.41 (0.26–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.32Z-score

OE missense 1.04 (0.97–1.11)

580 obs / 558.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.41 (0.26–0.67)

0≤0.351.4

Missense OE?1.04 (0.97–1.11)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 12 / 29.1Missense obs/exp: 580 / 558.4Syn Z: -0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveWHRN-related Usher syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6455th %ile

GOF

0.6541th %ile

LOF

0.51top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

956 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic21

VUS443

Likely Benign336

Benign49

Conflicting62

Pathogenic

Likely Pathogenic

443

VUS

336

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	36	0	0	0	36
Likely Pathogenic	19	1	1	0	21
VUS	3	394	38	8	443
Likely Benign	0	9	90	237	336
Benign	0	9	33	7	49
Conflicting	—				62
Total	58	413	162	252	947

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap WHRN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →