GeneBe

SEC63

protein-coding

SEC63 homolog, protein translocation regulator, the group of DNAJ (HSP40) heat shock proteins

Gene summary

The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER. [provided by RefSeq, Jul 2008]

MANE transcript

NM_007214.5

Inheritance

AD

ClinVar variants

P:70U:170B:62

Top phenotype

Polycystic liver disease 2 with or without kidney cysts

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr6:107,867,756-107,958,208

External References & Databases

Ensembl (ENSG00000025796)NCBI Gene (11231)OMIM (608648)HGNC:21082GenCCUniProt (Q9UGP8)AlphaFoldClinVar (SEC63)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~90.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polycystic liver disease 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014860

Submitter: Ambry Genetics

polycystic liver disease 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014860

Submitter: Labcorp Genetics (formerly Invitae)

polycystic liver disease 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014860

Submitter: ClinGen

SEC63 was FIRST reported in relation to autosomal dominant polycystic liver disease (ADPLD) in 2004 (Davila et al., PMID 15133510). ADPLD due to SEC63 mutations (ADPLD-SEC63) is diagnosed in adults with a family history of liver cysts, under age 40 with any number of liver cysts and individuals over the age of 40 with four or more liver cysts. Women are associated with more severe course of disease, and kidney cysts are present in approximately 28-35% of cases, but in these cases the kidney disease is mild with no association with progression to end stage renal disease (PMID 20408995). At least twenty unique variants (e.g. nonsense, frameshift, splice site, missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, population data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 19 probands and in at least four publications (PMID 15133510, PMID 16835903, PMID 20095989, PMID 28375157). Variants in this gene segregated with disease in at least 24 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function (PMID 15133510, PMID 20095989), with experimental evidence suggesting endoplasmic reticulum stress with induction of the unfolded protein response (UPR) and association with aberrant polycystin 1 (PC1) post-translational modifications leading to cystogenesis (PMID 22864019, PMID 25844898). This gene-disease association is supported by expression studies in cell models, zebrafish models, and mouse models (PMID 21685914, PMID 22864019, PMID 25844898). In summary, SEC63 is definitively associated with AUTOSOMAL DOMINANT POLYCYSTIC LIVER DISEASE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP on 09/23/2020 (SOP Version 7).

polycystic liver disease 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: Orphanet

polycystic liver disease 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014860

Submitter: Genomics England PanelApp

polycystic liver disease 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014860

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Polycystic liver disease 2 with or without kidney cystsAD

Manifestation: Gastrointestinal

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

Comments: Though some individuals may require treatment, it is unclear if early (genetic) diagnosis would be beneficial; Liver transplantion has been described

Refs: 15133510; 22099398; 23209713Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SEC63 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 251
Polycystic liver disease 2Total: 141
Inborn genetic diseasesTotal: 59
not specifiedTotal: 38
SEC63-related disorderTotal: 36
Autosomal dominant polycystic liver diseaseTotal: 27
Polycystic liver disease 1Total: 3
Biliary tract abnormalityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007214.5. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
45
clinvar
4
clinvar
 53
missense
6
clinvar
152
clinvar
13
clinvar
 171
nonsense
11
clinvar
10
clinvar
2
clinvar
 23
start loss
1
clinvar
 1
frameshift
11
clinvar
18
clinvar
6
clinvar
 35
splice donor/acceptor (+/-2bp)
2
clinvar
12
clinvar
5
clinvar
 19
Total2446170584302

Highest pathogenic variant AF is 0.000028467464

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_007214.5RefSeqNP_009145.121MANE Select
ENST00000369002.9EnsemblENSP00000357998.421MANE Select
ENST00000429168.1EnsemblENSP00000403144.17Standard
ENST00000446496.1EnsemblENSP00000410968.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
sec63Danio rerio

Structure: myelinating Schwann cell

Quality: swollen

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Protein export - Homo sapiens (human)
  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • XBP1(S) activates chaperone genes
  • IRE1alpha activates chaperones
  • Unfolded Protein Response (UPR)

Biological Process

  • liver development
  • protein targeting to membrane
  • SRP-dependent cotranslational protein targeting to membrane
  • posttranslational protein targeting to endoplasmic reticulum membrane
  • nitrogen compound metabolic process

Molecular Function

  • RNA binding
  • protein binding
  • protein transporter activity
  • signaling receptor activity

Cellular Component

  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • cytosol
  • membrane
  • integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000369002
Coding exons
21
Length
90434
Individuals with no LoFs
125710
Homozygous LoFs
0
Heterozygous LoFs
37
Defined
125747
p
0.000147
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.202753990.6900.00002015006
Missense (PolyPhen)52106.920.486341288
Synonymous-0.05901341331.010.000006251323
Loss of Function4.072153.00.3960.00000278610

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000950.000087rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000110.00011rare
Finnish0.000230.00023rare
European (Non-Finnish)0.000200.00018rare
South Asian00.0absent
Other0.000690.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) (PubMed:22375059, PubMed:29719251). Proposed to play an auxiliary role in recognition of precursors with short and apolar signal peptides. May cooperate with SEC62 and HSPA5/BiP to facilitate targeting of small presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen (PubMed:29719251). Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia (By similarity). {ECO:0000250|UniProtKB:Q8VHE0, ECO:0000269|PubMed:22375059, ECO:0000269|PubMed:29719251}.;

Recessive Scores

pRec
0.156

Intolerance Scores

LoFtool
0.731
RVIS EVS
-0.58
RVIS percentile EVS
18.72

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.643

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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