BICC1

protein-coding

BicC family RNA binding protein 1, the group of Sterile alpha motif domain containing

Gene summary

This gene encodes an RNA-binding protein that is active in regulating gene expression by modulating protein translation during embryonic development. Mouse studies identified the corresponding protein to be under strict control during cell differentiation and to be a maternally provided gene product. [provided by RefSeq, Apr 2009]

MANE transcript

NM_001080512.3

Inheritance

ClinVar variants

P:6U:265B:101

Top phenotype

Renal dysplasia, cystic, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr10:58,512,872-58,831,435

External References & Databases

Ensembl (ENSG00000122870)

Transcript & Mutation Effects

hg38 • Region Span ~318.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal dysplasia, cystic, susceptibility toLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011037

Submitter: Ambry Genetics

renal dysplasia, cystic, susceptibility toMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011037

Submitter: Broad Center for Mendelian Genomics

renal dysplasia, cystic, susceptibility toLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011037

Submitter: Labcorp Genetics (formerly Invitae)

renal dysplasia, cystic, susceptibility toMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011037

Submitter: ClinGen

*BICC1* was first reported in relation to incompletely penetrant autosomal-dominant CAKUT (congenital unilateral kidney dysplasia with contralateral renal hyperechogenicity) in 2012 (Kraus et al., PMID: 21922595). In OMIM, the following disease entity has been assigned: Susceptibility to renal dysplasia (OMIM:601331). In contrast to recessive Bicc1-mouse models (jcpk/bpk) and its association with several NPHPs (e.g. ANKS6), no cases of biallelic human *BICC1*-mutations with associated ciliopathies have been reported. Only three putative loss-of-function (LOF) variants (truncating, canonical splice site and missense with potential splice effect) have been reported in three non-related probands (PMID: 21922595, PMID: 35005812); all of which were included in this curation. However, two of these variants did not segregate and were identified through single gene candidate screening (PMID: 21922595). The third variant, which was found to be de novo, was associated with bilateral renal aganesis (CAKUT) (PMID: 35005812). Another two monoallelic candidate missense variants could not be scored in this curation for lack of functional and genetic evidence (PMID: 28566479). The mechanism of pathogenicity appears to be LOF or de novo with dysinhibition of Wnt-signaling (PMID: 21922595). This gene-disease association is also supported by experimental evidence (e.g. recessive animal models, expression studies, in vitro functional assays, etc.) (PMID: 12682776, PMID: 20215348, PMID: 29290488). In summary, due to the lack of genetic evidence, *BICC1* is only moderately associated with autosomal dominant CAKUT and cystic kidney disease with variable onset and expressivity. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 09/28/22 (SOP Version 8).

Clinical Genomic Database (CGD)

Renal dysplasia, cystic, susceptibility toAD

Manifestation: Renal

Intervention: Renal

Rationale: Sequelae can include vesicoureteral reflux, and early diagnosis could be helpful to institute measures to preserve kidney function

Refs: 21922595

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BICC1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 241

not specifiedTotal: 136

Renal dysplasia, cystic, susceptibility toTotal: 128

BICC1-related disorderTotal: 40

Congenital anomaly of kidney and urinary tractTotal: 1

Renal agenesisTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080512.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	64 clinvar	1 clinvar	74
missense			238 clinvar	32 clinvar	4 clinvar	274
nonsense		1 clinvar	6 clinvar			7
start loss						0
frameshift	1 clinvar	2 clinvar	6 clinvar			9
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	1	5	265	96	5	372

Highest pathogenic variant AF is 0.0000027367307

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080512.3	RefSeq	NP_001073981.1	21	MANE Select
ENST00000373886.8	Ensembl	ENSP00000362993.3	21	MANE Select
ENST00000263103.1	Ensembl	ENSP00000263103.1	10	Standard
ENST00001034774.1	Ensembl	ENSP00000704591.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

determination of left/right symmetry
heart development
negative regulation of canonical Wnt signaling pathway

Molecular Function

RNA binding

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373886
Coding exons: 21
Length: 318296
Individuals with no LoFs: 125710
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125730
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	449	530	0.848	0.0000270	6346
Missense (PolyPhen)		109	164.42	0.66292		2038
Synonymous	-0.440	205	197	1.04	0.0000105	1928
Loss of Function	5.24	10	50.0	0.200	0.00000283	584

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Putative RNA-binding protein. Acts as a negative regulator of Wnt signaling. May be involved in regulating gene expression during embryonic development. {ECO:0000269|PubMed:21922595}.;
Disease: DISEASE: Renal dysplasia, cystic (CYSRD) [MIM:601331]: An anomaly of the kidney characterized by numerous renal cysts and apparent disorder of differentiation of the renal parenchyma. Kidney of affected individuals lack the normal renal bean shape, and the collection drainage system. The cystic, dysplastic kidney contains undifferentiated mesenchyme, cartilaginous tissue, and immature collecting ducts. {ECO:0000269|PubMed:21922595}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.459
RVIS EVS: 0.6
RVIS percentile EVS: 82.87

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.153

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium