CRYM

Chr 16AD

crystallin mu

Also known as: DFNA40, THBP

NCBI Gene: 1428 ENSG00000103316 UniProt: Q14894 OMIM: 123740

The protein functions as an NADPH-dependent reductase that catalyzes the reduction of cyclic ketimine substrates, playing a central role in lysine and glutamate metabolism. Mutations cause autosomal dominant non-syndromic deafness (DFNA40). The gene is not highly constrained against loss-of-function variants, with hearing loss being the primary clinical manifestation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles. Mutations in this gene have been associated with autosomal dominant non-syndromic deafness. [provided by RefSeq, Sep 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.761 OMIM phenotype

Clinical Summary— CRYM

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

63 VUS of 149 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?

0.76LOEUF

pLI 0.026

Z-score 2.21

OE 0.36 (0.19–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.98Z-score

OE missense 0.79 (0.69–0.91)

138 obs / 174.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.19–0.76)

0≤0.351.4

Missense OE?0.79 (0.69–0.91)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 5 / 13.9Missense obs/exp: 138 / 174.6Syn Z: 0.89

This gene — mechanism propensity

0.6744th %ile

GOF

0.7126th %ile

LOF

0.2777th %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

149 submitted variants in ClinVar

ClinVar

Classification Summary

VUS63

Likely Benign43

Benign28

Conflicting11

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	5	51	7	0	63
Likely Benign	0	3	21	19	43
Benign	0	0	26	2	28
Conflicting	—				11
Total	5	54	54	21	145

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

View in ClinVar →

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