CST6

protein-coding

cystatin E/M, the group of Cystatins, type 2

Gene summary

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. This gene encodes a cystatin from the type 2 family, which is down-regulated in metastatic breast tumor cells as compared to primary tumor cells. Loss of expression is likely associated with the progression of a primary tumor to a metastatic phenotype. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001323.4

Inheritance

ClinVar variants

P:2U:22B:3

Top phenotype

Ectodermal dysplasia 15, hypohydrotic/hair type

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr11:66,012,008-66,013,505

External References & Databases

Ensembl (ENSG00000175315)

Transcript & Mutation Effects

hg38 • Region Span ~1.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ectodermal dysplasia 15, hypohidrotic/hair typeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032804

Submitter: Ambry Genetics

ectodermal dysplasia 15, hypohidrotic/hair typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032804

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Ectodermal dysplasia 15, hypohydrotic/hair typeAR

Manifestation: Dermatologic

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: 30425301

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CST6 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 22

Ectodermal dysplasia 15, hypohidrotic/hair typeTotal: 5

not providedTotal: 2

CST6-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001323.4. 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				1 clinvar		1
missense			21 clinvar	2 clinvar		23
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)						0
Total	1	1	22	3	0	27

Highest pathogenic variant AF is 6.843774e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001323.4	RefSeq	NP_001314.1	3	MANE Select
ENST00000312134.3	Ensembl	ENSP00000311313.2	3	MANE Select
ENST00001137691.1	Ensembl	ENSP00000806189.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vitamin D Receptor Pathway

Biological Process

epidermis development
anatomical structure morphogenesis
negative regulation of endopeptidase activity

Molecular Function

cysteine-type endopeptidase inhibitor activity

Cellular Component

cornified envelope
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000312134
Coding exons: 3
Length: 1665
Individuals with no LoFs: 114431
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 114432
p: 0.00000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	58	91.7	0.632	0.00000523	949
Missense (PolyPhen)		15	27.452	0.54641		309
Synonymous	-0.0857	42	41.3	1.02	0.00000259	305
Loss of Function	1.59	1	4.75	0.211	2.50e-7	51

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	0.000035	0.000035	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Shows moderate inhibition of cathepsin B but is not active against cathepsin C.;

Recessive Scores

pRec: 0.147

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.246

Gene Damage Prediction

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