SPECC1

Chr 17

sperm antigen with calponin homology and coiled-coil domains 1

Also known as: CYTSB, HCMOGT-1, HCMOGT1, NSP, NSP5

NCBI Gene: 92521 ENSG00000128487 UniProt: Q5M775

The SPECC1 protein is a nuclear-localized member of the cytospin-A family that is highly constrained against loss-of-function variants. Mutations cause Opitz G/BBB syndrome, an autosomal dominant disorder characterized by midline developmental defects including hypertelorism, cleft lip/palate, and genitourinary abnormalities. The gene's high constraint (pLI ~0.0009, LOEUF 0.49) reflects its critical role in normal midline development during embryogenesis.

ResearchSummary from RefSeq

The protein encoded by this gene belongs to the cytospin-A family. It is localized in the nucleus, and highly expressed in testis and some cancer cell lines. A chromosomal translocation involving this gene and platelet-derived growth factor receptor, beta gene (PDGFRB) may be a cause of juvenile myelomonocytic leukemia. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.49

Clinical Summary— SPECC1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 163 VUS of 200 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.001

Z-score 4.23

OE 0.32 (0.21–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.19Z-score

OE missense 1.02 (0.95–1.09)

619 obs / 606.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.32 (0.21–0.49)

0≤0.351.4

Missense OE?1.02 (0.95–1.09)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 14 / 44.4Missense obs/exp: 619 / 606.0Syn Z: -1.70

This gene — mechanism propensity

0.6550th %ile

GOF

0.5563th %ile

LOF

0.4331th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

200 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS163

Likely Benign9

Benign1

Conflicting1

Likely Pathogenic

163

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	1	0	0	1
VUS	0	163	0	0	163
Likely Benign	0	8	0	1	9
Benign	0	0	1	0	1
Conflicting	—				1
Total	0	172	1	1	175

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

View in ClinVar →

97 pathogenic / likely-pathogenic (of 118) ClinVar copy-number / structural variants overlap SPECC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →