GPSM2

protein-coding

G protein signaling modulator 2, the group of Tetratricopeptide repeat domain containing

Gene summary

The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Previous symbols:

DFNB82

MANE transcript

NM_013296.5

Inheritance

ClinVar variants

P:41U:162B:52

Top phenotype

Chudley-McCullough syndrome

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr1:108,875,350-108,934,545

External References & Databases

Ensembl (ENSG00000121957)

Transcript & Mutation Effects

hg38 • Region Span ~59.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Chudley-McCullough syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: ClinGen

The relationship between GPSM2 and autosomal recessive Chudley-McCullough syndrome was evaluated using the ClinGen Clinical Validity Framework as of 11/16/2017. Variants in GPSM2 were first reported in humans with this disease as early as 2010 (Walsh et al.). At least 8 nonsense and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 11 probands in 5 publications (23494849, 22578326, 27180139, 20602914, 21348867). Variants in this gene segregated with disease in 12 additional family members. Auditory testing and brain scans have lead to the diagnosis of Chudley-McCullough syndrome in each of these patients. This gene-disease association is supported by relevant expression studies and two mouse models. In summary, GPSM2 is definitively associated with autosomal recessive Chudley-McCullough syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Chudley-McCullough syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: Labcorp Genetics (formerly Invitae)

Chudley-McCullough syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: Genomics England PanelApp

Chudley-McCullough syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: Ambry Genetics

Chudley-McCullough syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: G2P

Chudley-McCullough syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: Orphanet

Chudley-McCullough syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011411

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Chudley-McCullough syndromeAR

Manifestation: Audiologic/Otolaryngologic; Neurologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 20602914; 20602914

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPSM2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 197

Inborn genetic diseasesTotal: 80

Chudley-McCullough syndromeTotal: 68

not specifiedTotal: 56

GPSM2-related disorderTotal: 32

Rare genetic deafnessTotal: 5

Hearing loss, autosomal recessiveTotal: 3

Fetal anomalies with a likely genetic causeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013296.5. 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	39 clinvar		44
missense		1 clinvar	147 clinvar	13 clinvar		161
nonsense	5 clinvar	8 clinvar	2 clinvar			15
start loss						0
frameshift	5 clinvar	11 clinvar	4 clinvar			20
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	4 clinvar			15
Total	11	30	162	52	0	255

Highest pathogenic variant AF is 0.0001940231

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013296.5	RefSeq	NP_037428.3	14	MANE Select
ENST00000264126.9	Ensembl	ENSP00000264126.3	14	MANE Select
NM_001321038.2	RefSeq	NP_001307967.1	14	Standard
NM_001321039.3	RefSeq	NP_001307968.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
G alpha (i) signalling events
GPCR downstream signalling

Biological Process

establishment of mitotic spindle orientation
mitotic spindle organization
G protein-coupled receptor signaling pathway
Ran protein signal transduction
regulation of catalytic activity

Molecular Function

nucleotide binding
G-protein alpha-subunit binding
GDP-dissociation inhibitor activity
protein binding
protein C-terminus binding

Cellular Component

cytoplasm
centrosome
cytosol
cell cortex
lateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000406462
Coding exons: 14
Length: 59196
Individuals with no LoFs: 125607
Homozygous LoFs: 0
Heterozygous LoFs: 141
Defined: 125748
p: 0.000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	297	364	0.815	0.0000188	4515
Missense (PolyPhen)		106	148.89	0.71196		1783
Synonymous	1.85	101	128	0.792	0.00000645	1280
Loss of Function	2.21	22	36.4	0.605	0.00000217	432

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00082	0.00082	rare
South Asian	0.00039	0.00039	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in mitotic spindle pole organization via its interaction with NUMA1 (PubMed:11781568, PubMed:15632202, PubMed:21816348). Required for cortical dynein- dynactin complex recruitment during metaphase (PubMed:22327364). Plays a role in metaphase spindle orientation (PubMed:22327364). Plays also an important role in asymmetric cell divisions (PubMed:21816348). Has guanine nucleotide dissociation inhibitor (GDI) activity towards G(i) alpha proteins, such as GNAI1 and GNAI3, and thereby regulates their activity (By similarity). {ECO:0000250|UniProtKB:Q8VDU0, ECO:0000269|PubMed:11781568, ECO:0000269|PubMed:15632202, ECO:0000269|PubMed:21816348, ECO:0000269|PubMed:22327364}.;

Intolerance Scores

LoFtool: 0.293
RVIS EVS: 0.02
RVIS percentile EVS: 55.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.769

Gene Damage Prediction

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