INVS

inversin, the group of Ankyrin repeat domain containing

Basic information

Region (hg38): 9:100099242-100302175

Previous symbols: [ "NPHP2" ]

Links

ENSG00000119509 ∙ NCBI:27130 ∙ OMIM:243305 ∙ HGNC:17870 ∙ Uniprot:Q9Y283 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nephronophthisis 2 (Definitive), mode of inheritance: AR
• Senior-Loken syndrome (Supportive), mode of inheritance: AR
• nephronophthisis 2 (Supportive), mode of inheritance: AR
• nephronophthisis 2 (Strong), mode of inheritance: AR
• nephronophthisis 2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Nephronophthisis 2	AR	General	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	Gastrointestinal; Neurologic; Renal	2702088; 9792867; 12872123; 19177160; 20798123; 23559409

ClinVar

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

• Nephronophthisis (646 variants)
• Infantile nephronophthisis (169 variants)
• not provided (147 variants)
• Inborn genetic diseases (39 variants)
• not specified (33 variants)
• INVS-related condition (7 variants)
• Kidney disorder (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the INVS 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			8	157	3	168
missense		1	322	7	1	331
nonsense	20	5	1			26
start loss						0
frameshift	24	5	1			30
inframe indel			7			7
splice donor/acceptor (+/-2bp)	2	12				14
splice region			16	18	1	35
non coding			20	63	27	110
Total	46	23	359	227	31

Highest pathogenic variant AF is 0.0000855

Variants in INVS

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

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

Position	Type	Phenotype	Significance	ClinVar
9-100099263-G-A		Infantile nephronophthisis	Uncertain significance (Jan 13, 2018)
9-100099265-C-T		Infantile nephronophthisis	Uncertain significance (Mar 30, 2018)
9-100099286-C-T		Infantile nephronophthisis	Likely benign (Jan 13, 2018)
9-100099312-C-A		Infantile nephronophthisis	Uncertain significance (Jan 13, 2018)
9-100099331-T-G		Infantile nephronophthisis • not specified • Nephronophthisis • Kidney disorder	Benign (Jan 29, 2024)
9-100104505-C-T		Infantile nephronophthisis	Conflicting classifications of pathogenicity (Aug 16, 2018)
9-100104527-C-A		Nephronophthisis	Uncertain significance (Sep 04, 2021)
9-100104531-T-G		Nephronophthisis	Uncertain significance (Oct 12, 2021)
9-100104548-T-C		Nephronophthisis	Likely benign (Jan 12, 2024)
9-100104554-T-C		Nephronophthisis	Conflicting classifications of pathogenicity (Apr 06, 2023)
9-100104560-A-G		Nephronophthisis	Likely benign (Oct 15, 2023)
9-100104569-A-G		Nephronophthisis	Likely benign (Jul 12, 2022)
9-100104569-A-T		Nephronophthisis	Likely benign (Sep 09, 2023)
9-100104587-C-A		Nephronophthisis	Likely benign (Dec 13, 2023)
9-100104587-C-T		Nephronophthisis	Likely benign (Jan 18, 2024)
9-100104588-G-A		Infantile nephronophthisis • Nephronophthisis	Uncertain significance (Sep 06, 2022)
9-100104588-G-C		Nephronophthisis	Uncertain significance (Jul 25, 2022)
9-100104601-AG-A		Nephronophthisis	Pathogenic (Aug 08, 2023)
9-100104609-C-T		Nephronophthisis	Likely benign (Feb 23, 2023)
9-100104611-A-G		Nephronophthisis	Likely benign (Dec 01, 2023)
9-100104613-A-G		Nephronophthisis	Uncertain significance (Oct 25, 2022)
9-100104617-G-A		Nephronophthisis • INVS-related disorder	Likely benign (Mar 23, 2023)
9-100104620-C-G		Nephronophthisis	Likely benign (May 05, 2023)
9-100104623-C-T		not specified • Nephronophthisis	Benign (Jan 31, 2024)
9-100104624-G-A		Nephronophthisis • Infantile nephronophthisis	Uncertain significance (Aug 20, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
INVS	protein_coding	protein_coding	ENST00000262457	16	201745

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.55e-18	0.728	125615	0	133	125748	0.000529

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.07	502	574	0.874	0.0000309	6960
Missense in Polyphen		131	181.79	0.72062		2250
Synonymous	0.649	204	216	0.944	0.0000117	2112
Loss of Function	2.02	35	50.5	0.693	0.00000293	581

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000886	0.000886
Ashkenazi Jewish	0.000498	0.000496
East Asian	0.000598	0.000598
Finnish	0.00	0.00
European (Non-Finnish)	0.000618	0.000615
Middle Eastern	0.000598	0.000598
South Asian	0.000523	0.000457
Other	0.00131	0.00130

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for normal renal development and establishment of left-right axis. Probably acts as a molecular switch between different Wnt signaling pathways. Inhibits the canonical Wnt pathway by targeting cytoplasmic disheveled (DVL1) for degradation by the ubiquitin-proteasome. This suggests that it is required in renal development to oppose the repression of terminal differentiation of tubular epithelial cells by Wnt signaling. Involved in the organization of apical junctions in kidney cells together with NPHP1, NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). {ECO:0000250, ECO:0000269|PubMed:15852005, ECO:0000269|PubMed:18371931}.
• Disease: DISEASE: Nephronophthisis 2 (NPHP2) [MIM:602088]: An autosomal recessive disorder resulting in end-stage renal disease. It is characterized by early onset and rapid progression. Phenotypic manifestations include enlarged kidneys, chronic tubulo- interstitial nephritis, anemia, hyperkalemic metabolic acidosis. Some patients also display situs inversus. Pathologically, it differs from later-onset nephronophthisis by the absence of medullary cysts and thickened tubular basement membranes, and by the presence of cortical microcysts. {ECO:0000269|PubMed:12872123}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Wnt signaling pathway - Homo sapiens (human);Wnt Signaling in Kidney Disease;Wnt Signaling Pathway (Consensus)

Recessive Scores

• pRec: 0.215

Intolerance Scores

• loftool: 0.912
• rvis_EVS: -0.57
• rvis_percentile_EVS: 19.04

Haploinsufficiency Scores

• pHI: 0.509
• hipred: Y
• hipred_score: 0.706
• ghis: 0.567

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.831

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Invs
• Phenotype: liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; 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); hematopoietic system 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); digestive/alimentary phenotype; renal/urinary system phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: invs
• Affected structure: pronephric proximal convoluted tubule
• Phenotype tag: abnormal
• Phenotype quality: increased diameter

Gene ontology

• Biological process: multicellular organism development;Wnt signaling pathway;negative regulation of canonical Wnt signaling pathway
• Cellular component: nucleus;cytoplasm;spindle;microtubule;cilium;membrane
• Molecular function: protein binding;calmodulin binding