TMTC2

protein-coding

transmembrane O-mannosyltransferase targeting cadherins 2, the group of Tetratricopeptide repeat domain containing|Transmembrane and tetratricopeptide repeat containing

Gene summary

The protein encoded by this gene is an integral membrane protein localized to the endoplasmic reticulum (ER). The encoded protein contains many tetratricopeptide repeats, sequences known for being involved in protein-protein interactions. This protein binds both the calcium uptake pump SERCA2B and the carbohydrate-binding chaperone calnexin, and it appears to play a role in calcium homeostasis in the ER. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

MANE transcript

NM_152588.3

Inheritance

AD, AR

ClinVar variants

U:119B:7

Top phenotype

TMTC2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr12:82,686,880-83,134,870

External References & Databases

Ensembl (ENSG00000179104)

Transcript & Mutation Effects

hg38 • Region Span ~448.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

*TMTC2* was first reported in relation to autosomal dominant nonsyndromic genetic hearing loss in 2016 (Runge et al., PMID: 27311106). 1 variant c.1141G>A (p.Val381Ile) that has been reported in 2 probands in 2 publications (PMIDs: 27311106, 29671961) is included in this curation. This variant is observed at a high allele frequency in gnomAD, 0.03761 (2561/251344) in South Asian exomes, bringing into question the pathogenicity of the variant. The mechanism of pathogenicity is reported to be LOF. In summary, *TMTC2* is classified as disputed in association with autosomal dominant nonsyndromic genetic hearing loss. It was reevaluated on 4/20/2022. This does not change the classification initially reached on 3/10/2017 when this gene-disease relationship was originally classified by the Hearing Loss GCEP.

hearing loss, autosomal recessive 122NO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0958228

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMTC2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 111

not providedTotal: 5

TMTC2-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152588.3. 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			2 clinvar	1 clinvar	2 clinvar	5
missense			112 clinvar	4 clinvar		116
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	119	5	2	126

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152588.3	RefSeq	NP_689801.1	12	MANE Select
ENST00000321196.8	Ensembl	ENSP00000322300.3	12	MANE Select
NM_001320321.2	RefSeq	NP_001307250.1	10	Standard
NM_001320322.2	RefSeq	NP_001307251.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

calcium ion homeostasis

Molecular Function

protein binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000321196
Coding exons: 12
Length: 447991
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125748
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.539	420	452	0.929	0.0000243	5463
Missense (PolyPhen)		123	157.53	0.7808		1794
Synonymous	-0.0488	178	177	1.00	0.00000982	1633
Loss of Function	3.97	10	35.6	0.281	0.00000178	461

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000098	0.000097	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Intolerance Scores

LoFtool: 0.336
RVIS EVS: 0.44
RVIS percentile EVS: 77.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.260

Gene Damage Prediction

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