SNAI2

protein-coding

snail family transcriptional repressor 2, the group of Zinc fingers C2H2-type|SNAG transcriptional repressors

Gene summary

This gene encodes a member of the Snail family of C2H2-type zinc finger transcription factors. The encoded protein acts as a transcriptional repressor that binds to E-box motifs and is also likely to repress E-cadherin transcription in breast carcinoma. This protein is involved in epithelial-mesenchymal transitions and has antiapoptotic activity. Mutations in this gene may be associated with sporatic cases of neural tube defects. [provided by RefSeq, Jul 2008]

Previous symbols:

SLUG

MANE transcript

NM_003068.5

Inheritance

AD, AR

ClinVar variants

U:51B:31

Top phenotype

Waardenburg syndrome, type 2D

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr8:48,917,598-48,921,740

External References & Databases

Ensembl (ENSG00000019549)

Transcript & Mutation Effects

hg38 • Region Span ~4.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

piebaldismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008244

Submitter: Orphanet

Waardenburg syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018094

Submitter: G2P

Waardenburg syndrome type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019517

Submitter: Orphanet

Waardenburg syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018094

Submitter: ClinGen

*SNAI2* was first reported in relation to autosomal recessive Waardenburg syndrome in 2002 (Sanchez-Martin et al., PMID: 12444107). A homozygous whole gene deletion has been reported in 2 probands in one study (PMIDs:12444107). This gene-disease relationship is also supported by a mouse model demonstrating abnormalities in the vestibular organ and cochlea of Slug-null mice, and a luciferase assay suggesting that MITF interacts with the SNAI2 promoter (PMID: 12444107). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 12/19/2017 as per SOP v5. It was reevaluated on 10/31/2024 using SOP v11. As a result of this reevaluation, this record underwent an update in scoring to be consistent with SOP v11. New case level evidence has been reviewed but was not scorable, and the classification did not change (PMID: 30936914).

piebaldismDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008244

Submitter: G2P

piebaldismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008244

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 2DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012144

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 2DMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012144

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Waardenburg syndrome, type 2DAR

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 1717985; 9450866; 12444107; 12955764

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SNAI2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 60

not specifiedTotal: 25

SNAI2-related disorderTotal: 10

PiebaldismTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003068.5. 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			4 clinvar	26 clinvar		30
missense			44 clinvar	4 clinvar	1 clinvar	49
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	51	30	1	82

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003068.5	RefSeq	NP_003059.1	3	MANE Select
ENST00000020945.4	Ensembl	ENSP00000020945.1	3	MANE Select
ENST00000396822.6	Ensembl	ENSP00000380034.2	2	Standard
ENST00001135105.1	Ensembl	ENSP00000801248.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adherens junction - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Neural Crest Differentiation
Glucocorticoid Receptor Pathway
Nuclear Receptors Meta-Pathway

Biological Process

negative regulation of transcription by RNA polymerase II
osteoblast differentiation
epithelial to mesenchymal transition
aortic valve morphogenesis
epithelial to mesenchymal transition involved in endocardial cushion formation

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA binding
chromatin binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396822
Coding exons: 3
Length: 4051
Individuals with no LoFs: 125538
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125539
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	101	139	0.725	0.00000686	1759
Missense (PolyPhen)		17	54.055	0.3145		665
Synonymous	-0.399	61	57.2	1.07	0.00000312	521
Loss of Function	2.57	1	9.60	0.104	4.57e-7	129

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	0.000046	0.000046	rare
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: Transcriptional repressor that modulates both activator- dependent and basal transcription. Involved in the generation and migration of neural crest cells. Plays a role in mediating RAF1- induced transcriptional repression of the TJ protein, occludin (OCLN) and subsequent oncogenic transformation of epithelial cells (By similarity). Represses BRCA2 expression by binding to its E2- box-containing silencer and recruiting CTBP1 and HDAC1 in breast cells. In epidermal keratinocytes, binds to the E-box in ITGA3 promoter and represses its transcription. Involved in the regulation of ITGB1 and ITGB4 expression and cell adhesion and proliferation in epidermal keratinocytes. Binds to E-box2 domain of BSG and activates its expression during TGFB1-induced epithelial-mesenchymal transition (EMT) in hepatocytes. Represses E-Cadherin/CDH1 transcription via E-box elements. Involved in osteoblast maturation. Binds to RUNX2 and SOC9 promoters and may act as a positive and negative transcription regulator, respectively, in osteoblasts. Binds to CXCL12 promoter via E-box regions in mesenchymal stem cells and osteoblasts. Plays an essential role in TWIST1-induced EMT and its ability to promote invasion and metastasis. {ECO:0000250, ECO:0000269|PubMed:10866665, ECO:0000269|PubMed:11912130, ECO:0000269|PubMed:15734731, ECO:0000269|PubMed:16707493, ECO:0000269|PubMed:19756381, ECO:0000269|PubMed:21182836}.;
Disease: DISEASE: Waardenburg syndrome 2D (WS2D) [MIM:608890]: WS2 is a genetically heterogeneous, autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, and absence of dystopia canthorum. The frequency of deafness is higher in WS2 than in WS1. {ECO:0000269|PubMed:12444107}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Piebald trait (PBT) [MIM:172800]: Autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. {ECO:0000269|PubMed:12955764}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.326

Intolerance Scores

RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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