KLLN

protein-coding

killin, p53 regulated DNA replication inhibitor

Gene summary

The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

MANE transcript

NM_001126049.2

Inheritance

ClinVar variants

U:56B:16

Top phenotype

Cowden syndrome 4

gnomAD constraint

pLI —, LoF o/e 1.15

Max pathogenic AF

—

Genomic locus

chr10:87,859,158-87,863,533

External References & Databases

Ensembl (ENSG00000227268)

NCBI Gene (100144748)

Transcript & Mutation Effects

hg38 • Region Span ~4.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Cowden syndrome 4NO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0014046

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cowden syndrome 4AD

Manifestation: Dermatologic; Oncologic

Intervention: Oncologic

Rationale: Individuals have been reported with a high risk of breast and renal cancer, and surveillance may allow early diagnosis and management of neoplastic processes

Comments: Germline hypermethylation and epigenetic inactivation of the KLLN promoter has been described in affected individuals

Refs: 21177507; 21956414

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLLN variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 65

not providedTotal: 8

KLLN-related disorderTotal: 4

Cowden syndrome 4Total: 3

PTEN hamartoma tumor syndromeTotal: 1

Cowden syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001126049.2. 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			4 clinvar	5 clinvar		9
missense			51 clinvar	10 clinvar		61
nonsense						0
start loss						0
frameshift			1 clinvar	1 clinvar		2
splice donor/acceptor (+/-2bp)						0
Total	0	0	56	16	0	72

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001126049.2	RefSeq	NP_001119521.1	1	MANE Select
ENST00000445946.5	Ensembl	ENSP00000392204.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

apoptotic process
cell cycle arrest

Molecular Function

DNA binding

Cellular Component

nucleus
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000445946
Coding exons: 1
Length: 4277
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.967	116	90.2	1.29	0.00000408	1109
Missense (PolyPhen)		38	26.776	1.4192		342
Synonymous	-2.09	55	38.5	1.43	0.00000176	403
Loss of Function	-0.219	3	2.62	1.15	1.12e-7	23

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis. Has the ability to inhibit DNA synthesis and S phase arrest coupled to apoptosis. Has affinity to both double- and single- stranded DNA. {ECO:0000269|PubMed:18385383}.;
Disease: DISEASE: Cowden syndrome 4 (CWS4) [MIM:615107]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. {ECO:0000269|PubMed:21177507}. Note=The gene represented in this entry is involved in disease pathogenesis. Germline KLLN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals (PubMed:21177507). {ECO:0000269|PubMed:21177507}.;

Intolerance Scores

RVIS EVS: 1.01
RVIS percentile EVS: 90.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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