GeneBe

SIX6

protein-coding

SIX homeobox 6, the group of SINE class homeoboxes

Gene summary

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]

Previous symbols:
  • OPTX2

MANE transcript

NM_007374.3

Inheritance

AR, AD

ClinVar variants

P:10U:72B:52

Top phenotype

Microphthalmia, isolated, with cataract 2; Optic disc anomalies with retinal and/or macular dystrophy

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr14:60,509,146-60,512,850

External References & Databases

Ensembl (ENSG00000184302)NCBI Gene (4990)OMIM (606326)HGNC:10892GenCCUniProt (O95475)AlphaFoldClinVar (SIX6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~3.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

colobomatous optic disc-macular atrophy-chorioretinopathy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008927

Submitter: Orphanet

colobomatous optic disc-macular atrophy-chorioretinopathy syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008927

Submitter: G2P

inherited retinal dystrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: Ambry Genetics

colobomatous optic disc-macular atrophy-chorioretinopathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008927

Submitter: G2P

colobomatous optic disc-macular atrophy-chorioretinopathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008927

Submitter: Labcorp Genetics (formerly Invitae)

colobomatous optic disc-macular atrophy-chorioretinopathy syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008927

Submitter: Ambry Genetics

colobomatous optic disc-macular atrophy-chorioretinopathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008927

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Microphthalmia, isolated, with cataract 2; Optic disc anomalies with retinal and/or macular dystrophyAD

Manifestation: Ophthalmologic

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: 15266624; 23167593; 24702266Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIX6 variants in ClinVar

13 Conditions Cataloged
not providedTotal: 103
not specifiedTotal: 29
Anophthalmia-microphthalmia syndromeTotal: 15
Colobomatous optic disc-macular atrophy-chorioretinopathy syndromeTotal: 10
SIX6-related disorderTotal: 7
Developmental cataractTotal: 2
Anophthalmia/microphthalmia-esophageal atresia syndromeTotal: 2
SclerocorneaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007374.3. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
47
clinvar
1
clinvar
 51
missense
2
clinvar
2
clinvar
64
clinvar
4
clinvar
 72
nonsense
2
clinvar
2
clinvar
 4
start loss
1
clinvar
 1
frameshift
2
clinvar
3
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total4672511134

Highest pathogenic variant AF is 0.00007623236

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_007374.3RefSeqNP_031400.22MANE Select
ENST00000327720.6EnsemblENSP00000328596.52MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
six6bDanio rerio

Structure: mandibular arch skeleton

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ectoderm Differentiation

Biological Process

  • eye development
  • visual perception
  • animal organ morphogenesis
  • negative regulation of transcription, DNA-templated
  • positive regulation of transcription by RNA polymerase II

Molecular Function

  • transcription regulatory region sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific

Cellular Component

  • nucleus
  • transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000327720
Coding exons
2
Length
3900
Individuals with no LoFs
125730
Homozygous LoFs
0
Heterozygous LoFs
12
Defined
125742
p
0.0000477
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.7141171410.8310.000006341550
Missense (PolyPhen)3050.4090.59514564
Synonymous0.9385564.60.8520.00000303529
Loss of Function2.44210.60.1894.75e-7100

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000690.000062rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000450.000044rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May be involved in eye development.;

Recessive Scores

pRec
0.125

Intolerance Scores

LoFtool
0.223
RVIS EVS
0.68
RVIS percentile EVS
84.93

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.928

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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