GeneBe

SGMS2

protein-coding

sphingomyelin synthase 2

Gene summary

Sphingomyelin, a major component of cell and Golgi membranes, is made by the transfer of phosphocholine from phosphatidylcholine onto ceramide, with diacylglycerol as a side product. The protein encoded by this gene is an enzyme that catalyzes this reaction primarily at the cell membrane. The synthesis is reversible, and this enzyme can catalyze the reaction in either direction. The encoded protein is required for cell growth. Three transcript variants encoding the same protein have been found for this gene. There is evidence for more variants, but the full-length nature of their transcripts has not been determined.[provided by RefSeq, Oct 2008]

MANE transcript

NM_001375905.1

Inheritance

AD

ClinVar variants

P:4U:101B:55

Top phenotype

Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr4:107,824,563-107,915,047

External References & Databases

Ensembl (ENSG00000164023)NCBI Gene (166929)OMIM (611574)HGNC:28395GenCCUniProt (Q8NHU3)AlphaFoldClinVar (SGMS2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~90.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

calvarial doughnut lesions-bone fragility syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007470

Submitter: Ambry Genetics

calvarial doughnut lesions-bone fragility syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007470

Submitter: Labcorp Genetics (formerly Invitae)

calvarial doughnut lesions-bone fragility syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007470

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasiaAD

Manifestation: Musculoskeletal

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: 30779713Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SGMS2 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 140
Inborn genetic diseasesTotal: 36
not specifiedTotal: 17
SGMS2-related disorderTotal: 8
Calvarial doughnut lesions-bone fragility syndromeTotal: 8
Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasiaTotal: 2
Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001375905.1. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
43
clinvar
4
clinvar
 48
missense
2
clinvar
92
clinvar
8
clinvar
 102
nonsense
2
clinvar
2
clinvar
 4
start loss
1
clinvar
 1
frameshift
4
clinvar
 4
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total22101514160

Highest pathogenic variant AF is 0.000017103326

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001375905.1RefSeqNP_001362834.15MANE Select
ENST00000690982.1EnsemblENSP00000508566.15MANE Select
NM_001136257.2RefSeqNP_001129729.15Standard
NM_001136258.2RefSeqNP_001129730.15Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Sphingolipid signaling pathway - Homo sapiens (human)
  • Sphingolipid metabolism - Homo sapiens (human)
  • Metabolism of lipids
  • sphingomyelin metabolism/ceramide salvage
  • Metabolism

Biological Process

  • sphingomyelin biosynthetic process
  • phosphorylation
  • sphingolipid biosynthetic process
  • ceramide biosynthetic process
  • ceramide phosphoethanolamine biosynthetic process

Molecular Function

  • ceramide phosphoethanolamine synthase activity
  • kinase activity
  • sphingomyelin synthase activity
  • ceramide cholinephosphotransferase activity

Cellular Component

  • Golgi apparatus
  • plasma membrane
  • integral component of plasma membrane
  • integral component of Golgi membrane
  • integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000394684
Coding exons
5
Length
90485
Individuals with no LoFs
125677
Homozygous LoFs
0
Heterozygous LoFs
35
Defined
125712
p
0.000139
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.101612050.7840.00001122367
Missense (PolyPhen)6487.5730.73082943
Synonymous-0.6548476.71.090.00000436705
Loss of Function2.97620.50.2930.00000122219

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.000190.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000180.00018rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Sphingomyelin synthases synthesize the sphingolipid, sphingomyelin, through transfer of the phosphatidyl head group, phosphatidylcholine, on to the primary hydroxyl of ceramide. The reaction is bidirectional depending on the respective levels of the sphingolipid and ceramide. Plasma membrane SMS2 can also convert phosphatidylethanolamine (PE) to ceramide phosphatidylethanolamine (CPE). Major form in liver. Required for cell growth in certain cell types. Regulator of cell surface levels of ceramide, an important mediator of signal transduction and apoptosis. Regulation of sphingomyelin (SM) levels at the cell surface affects insulin sensitivity. {ECO:0000269|PubMed:14685263, ECO:0000269|PubMed:17449912}.;

Recessive Scores

pRec
0.133

Intolerance Scores

LoFtool
0.808
RVIS EVS
0.02
RVIS percentile EVS
55.22

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.890

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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