SERPINB6

protein-coding

serpin family B member 6, the group of Serpin peptidase inhibitors

Gene summary

The protein encoded by this gene is a member of the serpin (serine proteinase inhibitor) superfamily, and ovalbumin(ov)-serpin subfamily. It was originally discovered as a placental thrombin inhibitor. The mouse homolog was found to be expressed in the hair cells of the inner ear. Mutations in this gene are associated with nonsyndromic progressive hearing loss, suggesting that this serpin plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

Previous symbols:

PI6
DFNB91

MANE transcript

NM_004568.6

Inheritance

ClinVar variants

P:5U:97B:50

Top phenotype

Deafness, autosomal recessive 91

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr6:2,948,159-2,972,165

External References & Databases

Ensembl (ENSG00000124570)

Transcript & Mutation Effects

hg38 • Region Span ~24.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 91STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013269

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 91STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013269

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 91LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013269

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 91DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013269

Submitter: G2P

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

SERPINB6 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2010 (Sirmaci et al., PMID: 20451170). Four variants (missense, nonsense, frameshift, and canonical splice site) that have been reported in two probands in two publications (PMIDs: 20451170, 25719458, 33997018) are included in this curation. Variants in SERPINB6 were shown to segregate with disease as well. The mechanism of pathogenicity is known to be LOF. This gene-disease relationship is also supported by expression in the developing inner ear, altered expression in patients, functional alteration in patients, and a mouse model phenocopying disease (PMIDs: 20451170, 23669344). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 10/5/2017 and reviewed again on 4/24/2018. It was reevaluated on 10/19/2022. As a result of this reevaluation, the classification did not change from moderate (SOP Version 9).

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 91AR

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 20451170; 24963352

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINB6 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 130

not specifiedTotal: 93

SERPINB6-related disorderTotal: 26

Autosomal recessive nonsyndromic hearing loss 91Total: 9

Rare genetic deafnessTotal: 1

Hearing impairmentTotal: 1

Usher syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004568.6. 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			2 clinvar	33 clinvar	1 clinvar	36
missense		1 clinvar	92 clinvar	15 clinvar	1 clinvar	109
nonsense	1 clinvar	2 clinvar	1 clinvar			4
start loss		1 clinvar				1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	4	97	48	2	152

Highest pathogenic variant AF is 0.000041511874

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 198 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004568.6	RefSeq	NP_004559.4	6	MANE Select
ENST00000380539.7	Ensembl	ENSP00000369912.2	6	MANE Select
NM_001195291.3	RefSeq	NP_001182220.2	7	Standard
NM_001271822.2	RefSeq	NP_001258751.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Amoebiasis - Homo sapiens (human)
Ectoderm Differentiation
Neutrophil degranulation
Dissolution of Fibrin Clot
Innate Immune System

Biological Process

sensory perception of sound
negative regulation of endopeptidase activity
neutrophil degranulation
cellular response to osmotic stress

Molecular Function

protease binding
serine-type endopeptidase inhibitor activity

Cellular Component

extracellular region
extracellular space
nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380520
Coding exons: 6
Length: 23698
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0613	214	217	0.988	0.0000130	2528
Missense (PolyPhen)		56	69.793	0.80237		902
Synonymous	-0.522	92	85.8	1.07	0.00000613	689
Loss of Function	1.27	8	12.9	0.618	5.61e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in the regulation of serine proteinases present in the brain or extravasated from the blood (By similarity). Inhibitor of cathepsin G, kallikrein-8 and thrombin. May play an important role in the inner ear in the protection against leakage of lysosomal content during stress and loss of this protection results in cell death and sensorineural hearing loss. {ECO:0000250, ECO:0000269|PubMed:10068683, ECO:0000269|PubMed:17761692, ECO:0000269|PubMed:20451170, ECO:0000269|PubMed:8136380, ECO:0000269|PubMed:8415716}.;

Intolerance Scores

LoFtool: 0.186
RVIS EVS: -0.14
RVIS percentile EVS: 43.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.494

Gene Damage Prediction

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