SIX2

SIX homeobox 2, the group of SINE class homeoboxes

Basic information

Region (hg38): 2:45005182-45009452

Links

ENSG00000170577 ∙ NCBI:10736 ∙ OMIM:604994 ∙ HGNC:10888 ∙ Uniprot:Q9NPC8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SIX2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIX2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				20	2	22
missense		1	34	1	2	38
nonsense						0
start loss			1			1
frameshift						0
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding				2	2	4
Total	0	1	37	23	6

Variants in SIX2

This is a list of pathogenic ClinVar variants found in the SIX2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-45006164-T-C		SIX2-related disorder	Likely benign (Dec 08, 2022)
2-45006181-G-C		not specified	Uncertain significance (May 02, 2024)
2-45006187-C-A		not specified	Uncertain significance (Sep 03, 2024)
2-45006187-C-T			Uncertain significance (Dec 07, 2021)
2-45006193-T-G		SIX2-related disorder	Benign (Jul 17, 2020)
2-45006207-T-C		SIX2-related disorder • not specified	Uncertain significance (Aug 27, 2024)
2-45006209-G-A			Likely benign (Jun 23, 2022)
2-45006224-C-A			Likely benign (Nov 27, 2023)
2-45006228-C-T		not specified	Uncertain significance (Dec 11, 2023)
2-45006248-G-A			Likely benign (Jul 09, 2022)
2-45006251-C-T			Benign (Jul 22, 2023)
2-45006252-G-A		not specified	Uncertain significance (Jun 25, 2024)
2-45006255-C-T			Uncertain significance (Jun 24, 2024)
2-45006263-G-A			Likely benign (Mar 23, 2024)
2-45006265-C-T		not specified	Uncertain significance (Dec 02, 2022)
2-45006272-C-G		SIX2-related disorder	Likely benign (Jul 24, 2024)
2-45006273-G-A		not specified	Uncertain significance (Feb 21, 2025)
2-45006282-A-G			Benign (Jun 28, 2024)
2-45006284-T-A			Likely benign (Sep 24, 2024)
2-45006286-C-T			Likely pathogenic (Feb 08, 2017)
2-45006287-G-A			Benign (Oct 11, 2024)
2-45006287-G-T		not specified	Uncertain significance (Mar 28, 2024)
2-45006289-T-C		not specified	Uncertain significance (Sep 26, 2024)
2-45006296-C-G			Likely benign (Jan 01, 2022)
2-45006297-G-A		not specified	Uncertain significance (Nov 21, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SIX2	protein_coding	protein_coding	ENST00000303077	2	4270

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.939	0.0611	125722	0	9	125731	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.519	146	165	0.886	0.00000881	1875
Missense in Polyphen		28	50.741	0.55182		603
Synonymous	-1.24	90	76.2	1.18	0.00000453	610
Loss of Function	2.76	0	8.86	0.00	3.96e-7	94

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000206	0.000206
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00000887	0.00000879
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach. During kidney development, maintains cap mesenchyme multipotent nephron progenitor cells in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud and cooperates with WNT9B to promote renewing progenitor cells proliferation. Acts through its interaction with TCF7L2 and OSR1 in a canonical Wnt signaling independent manner preventing transcription of differentiation genes in cap mesenchyme such as WNT4. Also acts independently of OSR1 to activate expression of many cap mesenchyme genes, including itself, GDNF and OSR1. During craniofacial development plays a role in growth and elongation of the cranial base through regulation of chondrocyte differentiation. During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1. During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway. Also may be involved in limb tendon and ligament development (By similarity). Plays a role in cell proliferation and migration. {ECO:0000250|UniProtKB:Q62232, ECO:0000269|PubMed:22995329}.

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.0370
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.53

Haploinsufficiency Scores

• pHI: 0.892
• hipred: Y
• hipred_score: 0.837
• ghis: 0.481

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.166

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Six2
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; renal/urinary system phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: six2a
• Affected structure: pronephric glomerulus
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: kidney development;chondrocyte differentiation;mesenchymal to epithelial transition involved in metanephros morphogenesis;protein import into nucleus;mesodermal cell fate specification;cell population proliferation;anatomical structure morphogenesis;anterior/posterior axis specification;cell migration;regulation of ossification;regulation of chondrocyte differentiation;middle ear morphogenesis;negative regulation of cell differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;embryonic digestive tract morphogenesis;embryonic cranial skeleton morphogenesis;anatomical structure development;nephron development;nephron morphogenesis;mesenchymal stem cell maintenance involved in nephron morphogenesis;condensed mesenchymal cell proliferation;mesenchymal cell differentiation involved in kidney development;regulation of branching involved in ureteric bud morphogenesis;mesenchymal stem cell proliferation;positive regulation of chondrocyte proliferation
• Cellular component: nucleus;transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;transcription factor binding;protein-containing complex binding