BFSP2

Chr 3AD

beaded filament structural protein 2

Also known as: CP47, CP49, CTRCT12, LIFL-L, PHAKOSIN

NCBI Gene: 8419 ENSG00000170819 UniProt: Q13515 OMIM: 603212

BFSP2 encodes phakinin, a lens-specific intermediate filament protein required for correct formation of lens intermediate filaments and maintenance of lens optical clarity. Mutations cause autosomal dominant Cataract 12, which presents with juvenile-onset, progressive cataracts. The gene is highly intolerant to loss-of-function mutations (pLI near 0), indicating it is essential for normal lens function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

More than 99% of the vertebrate ocular lens is comprised of terminally differentiated lens fiber cells. Two lens-specific intermediate filament-like proteins, the protein product of this gene (phakinin), and filensin, are expressed only after fiber cell differentiation has begun. Both proteins are found in a structurally unique cytoskeletal element that is referred to as the beaded filament (BF). Mutations in this gene have been associated with juvenile-onset, progressive cataracts and Dowling-Meara epidermolysis bullosa simplex. [provided by RefSeq, Jun 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.041 OMIM phenotype

Clinical Summary— BFSP2

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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

4 unique Pathogenic / Likely Pathogenic· 90 VUS of 162 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?

1.04LOEUF

pLI 0.000

Z-score 1.42

OE 0.67 (0.45–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.29Z-score

OE missense 0.95 (0.85–1.06)

239 obs / 252.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.45–1.04)

0≤0.351.4

Missense OE?0.95 (0.85–1.06)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 15 / 22.3Missense obs/exp: 239 / 252.0Syn Z: 0.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBFSP2-related cataractOTHERAR

definitiveBFSP2-related cataractOTHERAD

This gene — mechanism propensity

0.89top 5%

GOF

0.84top 5%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

162 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS90

Likely Benign25

Benign33

Conflicting7

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	1	0	4
Likely Pathogenic	0	0	0	0	0
VUS	2	78	6	4	90
Likely Benign	0	4	15	6	25
Benign	0	4	21	8	33
Conflicting	—				7
Total	4	87	43	18	159

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap BFSP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →