SGMS2

sphingomyelin synthase 2

Basic information

Region (hg38): 4:107824563-107915047

Links

ENSG00000164023 ∙ NCBI:166929 ∙ OMIM:611574 ∙ HGNC:28395 ∙ Uniprot:Q8NHU3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• calvarial doughnut lesions-bone fragility syndrome (Moderate), mode of inheritance: AD
• calvarial doughnut lesions-bone fragility syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia	AD	General	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	Musculoskeletal	30779713

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SGMS2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SGMS2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	27	5	33
missense			55	4	1	60
nonsense		2	1			3
start loss			1			1
frameshift			2			2
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			1	1	1	3
non coding				5	7	12
Total	0	2	61	36	13

Variants in SGMS2

This is a list of pathogenic ClinVar variants found in the SGMS2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-107895554-A-G			Uncertain significance (Sep 05, 2024)
4-107895564-T-C			Uncertain significance (Apr 24, 2023)
4-107895570-C-G			Uncertain significance (Dec 18, 2024)
4-107895570-C-T			Uncertain significance (Oct 22, 2024)
4-107895572-G-C		Inborn genetic diseases	Uncertain significance (Dec 26, 2024)
4-107895573-C-A			Uncertain significance (Jul 18, 2022)
4-107895583-A-C		Inborn genetic diseases	Uncertain significance (Mar 15, 2024)
4-107895594-A-C		Inborn genetic diseases	Uncertain significance (Nov 15, 2024)
4-107895603-C-T		Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
4-107895606-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 23, 2024)
4-107895615-C-T			Benign (Jan 21, 2025)
4-107895616-G-A			Likely benign (Oct 08, 2022)
4-107895622-T-G			Benign (Aug 23, 2023)
4-107895634-C-T			Likely benign (Oct 29, 2024)
4-107895635-G-A			Uncertain significance (Apr 18, 2024)
4-107895656-A-G			Uncertain significance (Feb 17, 2024)
4-107895669-A-G			Uncertain significance (Oct 16, 2022)
4-107895672-G-A			Uncertain significance (Oct 12, 2024)
4-107895676-A-G			Uncertain significance (Jun 30, 2023)
4-107895701-C-T		Calvarial doughnut lesions-bone fragility syndrome • Inborn genetic diseases • Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia	Pathogenic/Likely pathogenic (Dec 14, 2024)
4-107895702-G-A		Inborn genetic diseases	Uncertain significance (Oct 19, 2024)
4-107895711-C-A			Uncertain significance (Apr 25, 2023)
4-107895712-C-T			Likely benign (Sep 01, 2024)
4-107895714-A-G			Likely benign (Oct 09, 2024)
4-107895720-A-T			Uncertain significance (Jan 07, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SGMS2	protein_coding	protein_coding	ENST00000394684	5	90485

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0569	0.942	125677	0	35	125712	0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.10	161	205	0.784	0.0000112	2367
Missense in Polyphen		64	87.573	0.73082		943
Synonymous	-0.654	84	76.7	1.09	0.00000436	705
Loss of Function	2.97	6	20.5	0.293	0.00000122	219

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000374	0.000373
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000177	0.000176
Middle Eastern	0.000163	0.000163
South Asian	0.00	0.00
Other	0.000164	0.000163

dbNSFP

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}.
• Pathway: Sphingolipid signaling pathway - Homo sapiens (human);Sphingolipid metabolism - Homo sapiens (human);Metabolism of lipids;sphingomyelin metabolism/ceramide salvage;Metabolism;Sphingolipid de novo biosynthesis;Sphingolipid metabolism (Consensus)

Recessive Scores

• pRec: 0.133

Intolerance Scores

• loftool: 0.808
• rvis_EVS: 0.02
• rvis_percentile_EVS: 55.22

Haploinsufficiency Scores

• pHI: 0.317
• hipred: Y
• hipred_score: 0.554
• ghis: 0.398

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.890

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sgms2
• Phenotype: immune system phenotype; hematopoietic system phenotype; liver/biliary system phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype

Gene ontology

• Biological process: sphingomyelin biosynthetic process;phosphorylation;sphingolipid biosynthetic process;ceramide biosynthetic process;ceramide phosphoethanolamine biosynthetic process
• Cellular component: Golgi apparatus;plasma membrane;integral component of plasma membrane;integral component of Golgi membrane;integral component of endoplasmic reticulum membrane
• Molecular function: ceramide phosphoethanolamine synthase activity;kinase activity;sphingomyelin synthase activity;ceramide cholinephosphotransferase activity