ANKS6

protein-coding

ankyrin repeat and sterile alpha motif domain containing 6, the group of Ankyrin repeat domain containing|Sterile alpha motif domain containing

Gene summary

This gene encodes a protein containing multiple ankyrin repeats and a SAM domain. It is thought that this protein may localize to the proximal region of the primary cilium, and may play a role in renal and cardiovascular development. Mutations in this gene have been shown to cause a form of nephronophthisis (NPHP16), a chronic tubulo-interstitial nephritis. [provided by RefSeq, Jul 2015]

Previous symbols:

SAMD6
ANKRD14

MANE transcript

NM_173551.5

Inheritance

ClinVar variants

P:43U:326B:157

Top phenotype

Nephronophthisis 16

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr9:98,731,329-98,796,965

External References & Databases

Ensembl (ENSG00000165138)

Transcript & Mutation Effects

hg38 • Region Span ~65.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephronophthisis 16DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014158

Submitter: ClinGen

Biallelic ANKS6 pathogenic variants were first reported in relation to autosomal recessive cystic kidney disease in 2013 (Hoff et al., PMID: 23793029) and have been associated with Nephronophthisis 16 (OMIM #615382). ANKS6 is a critical component of the ciliary complex required for kidney and cardiovascular development and affected patients develop progressive kidney dysfunction that may or may not be accompanied by extrarenal manifestations, including hypertrophic obstructive cardiomyopathy, aortic stenosis, pulmonary stenosis, patent ductus arteriosus, situs inversus, and periportal liver fibrosis. At least 8 variants (3 frameshift, 3 splice, 2 missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands in 5 publications (PMIDs: 23793029; 31678577; 31635528, 24610927, 26489029). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be biallelic loss of function. This gene-disease association is supported by animal models, expression studies, and protein interactions (PMIDs: 26039630, 25599650, 23793029). In summary, ANKS6 is definitively associated with autosomal recessive nephronophthisis (NPHP-ANKS6). 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 08/25/21 (SOP Version 8).

nephronophthisis 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009728

Submitter: Orphanet

nephronophthisis 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Orphanet

nephronophthisis 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014158

Submitter: Labcorp Genetics (formerly Invitae)

nephronophthisis 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014158

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Nephronophthisis 16AR

Manifestation: Cardiovascular; Gastrointestinal; Renal

Intervention: Cardiovascular

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Comments: Renal transplant has been described

Refs: 23793029

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANKS6 variants in ClinVar

5 Conditions Cataloged

Nephronophthisis 16Total: 438

Inborn genetic diseasesTotal: 158

not providedTotal: 128

ANKS6-related disorderTotal: 66

not specifiedTotal: 43

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173551.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	126 clinvar	1 clinvar	132
missense		3 clinvar	310 clinvar	27 clinvar	3 clinvar	343
nonsense	5 clinvar	8 clinvar	3 clinvar			16
start loss						0
frameshift	12 clinvar	9 clinvar	2 clinvar			23
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	6 clinvar			12
Total	19	24	326	153	4	526

Highest pathogenic variant AF is 0.00003965918

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173551.5	RefSeq	NP_775822.3	15	MANE Select
ENST00000353234.5	Ensembl	ENSP00000297837.6	15	MANE Select
ENST00000375019.6	Ensembl	ENSP00000364159.2	14	Standard
ENST00000375019.7	Ensembl	ENSP00000364159.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Molecular Function

protein binding

Cellular Component

cytoplasm
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000353234
Coding exons: 15
Length: 65637
Individuals with no LoFs: 124731
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 124797
p: 0.000264

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0756	463	458	1.01	0.0000279	5561
Missense (PolyPhen)		130	147.33	0.88238		1742
Synonymous	0.121	199	201	0.989	0.0000139	1865
Loss of Function	2.89	14	31.5	0.444	0.00000168	380

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00028	0.00027	rare
South Asian	0.00064	0.00059	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for renal function. {ECO:0000269|PubMed:23793029}.;
Disease: DISEASE: Nephronophthisis 16 (NPHP16) [MIM:615382]: A form of nephronophthisis, a chronic tubulo-interstitial nephritis that progresses to end-stage renal failure. Some patients have cystic kidneys of normal size and no extrarenal manifestations, whereas others have enlarged renal size and severe extrarenal defects, including hypertrophic obstructive cardiomyopathy, aortic stenosis, pulmonary stenosis, patent ductus arteriosus, situs inversus, and periportal liver fibrosis. {ECO:0000269|PubMed:23793029}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.678
RVIS EVS: -0.35
RVIS percentile EVS: 29.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.339

Gene Damage Prediction

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