BICRA

Chr 19AD

BRD4 interacting chromatin remodeling complex associated protein

Also known as: CSS12, GLTSCR1, SMARCK1

NCBI Gene: 29998 ENSG00000063169 UniProt: Q9NZM4 OMIM: 605690

The BICRA protein is a component of the SWI/SNF chromatin remodeling complex that alters DNA-histone contacts within nucleosomes in an ATP-dependent manner to regulate gene transcription. Mutations cause Coffin-Siris syndrome 12, a neurodevelopmental disorder with intellectual disability and distinctive facial features, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.98), indicating that most pathogenic variants are likely de novo mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables transcription regulator activator activity. Involved in positive regulation of DNA-templated transcription. Located in nucleus. Part of SWI/SNF complex. Implicated in Coffin-Siris syndrome 12. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Coffin-Siris syndrome 12MIM #619325

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Coffin-Siris syndrome · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — BICRA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.983

Z-score 4.66

OE 0.14 (0.07–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.54Z-score

OE missense 0.75 (0.70–0.80)

618 obs / 823.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.30)

0≤0.351.4

Missense OE?0.75 (0.70–0.80)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 5 / 34.5Missense obs/exp: 618 / 823.0Syn Z: -1.41

Background carrier burden — how many people carry a rare variant somewhere in BICRA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 23

2,441 rare PASS variants

Rare truncating (LoF)

1 in 280

220 rare PASS variants

Rare synonymous (reference)

1 in 30

1,442 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BICRA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 28	1 in 190
South Asian	~43k	1 in 25	1 in 320
Remaining (unassigned)	~30k	1 in 21	1 in 190
European (Finnish)	~27k	1 in 61	1 in 210
Admixed American	~22k	1 in 26	1 in 460
African / African American	~21k	1 in 23	1 in 380
East Asian	~20k	1 in 31	1 in 460
Ashkenazi Jewish	~13k	1 in 100	1 in 510
Middle Eastern	~2,884	1 in 30	1 in 260

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.