SMN2
protein-codingsurvival of motor neuron 2, centromeric, the group of Tudor domain containing|SMN complex
Gene summary
This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The full length protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Four transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Sep 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009672
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
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
Comments: Variants in SMN2 are most important in the context of individuals with SMN1 variants
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMN2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017411.4. 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 | 1 | 3 | |||
| missense | 1 | 1 | 2 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 1 | 4 | 1 | 6 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_059107.1 | 8 | MANE Select | |
| Ensembl | ENSP00000370119.4 | 8 | MANE Select | |
| RefSeq | NP_075013.1 | 8 | Standard | |
| RefSeq | NP_075014.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA transport - Homo sapiens (human)
- snRNP Assembly
- Metabolism of RNA
- Metabolism of non-coding RNA
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380743
- Coding exons
- 8
- Length
- 29000
- Individuals with no LoFs
- 112942
- Homozygous LoFs
- 9
- Heterozygous LoFs
- 12
- Defined
- 112963
- p
- 0.0000930
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.440 | 4 | 7.36 | 0.544 | 3.08e-7 | 1912 |
| Missense (PolyPhen) | 2 | 2.3345 | 0.85671 | 801 | ||
| Synonymous | -0.961 | 4 | 2.19 | 1.83 | 9.35e-8 | 565 |
| Loss of Function | 0.202 | 1 | 1.24 | 0.804 | 5.18e-8 | 207 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0019 | 0.0012 | notable |
| Latino/Admixed American | 0.000064 | 0.000064 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000098 | 0.0000098 | rare |
| South Asian | 0.00011 | 0.00011 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The SMN complex plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Thereby, plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP. In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. Dissociation by the SMN complex of CLNS1A from the trapped Sm proteins and their transfer to an SMN-Sm complex triggers the assembly of core snRNPs and their transport to the nucleus. Ensures the correct splicing of U12 intron-containing genes that may be important for normal motor and proprioceptive neurons development. Also required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs). {ECO:0000269|PubMed:18984161, ECO:0000269|PubMed:23063131, ECO:0000269|PubMed:26700805, ECO:0000269|PubMed:9845364}.;
- Disease
- DISEASE: Spinal muscular atrophy 1 (SMA1) [MIM:253300]: A form of spinal muscular atrophy, a group of neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Autosomal recessive forms are classified according to the age of onset, the maximum muscular activity achieved, and survivorship. The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7- skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. SMA1 is a severe form, with onset before 6 months of age. SMA1 patients never achieve the ability to sit. {ECO:0000269|PubMed:10732817, ECO:0000269|PubMed:14715275, ECO:0000269|PubMed:15249625, ECO:0000269|PubMed:15580564, ECO:0000269|PubMed:7813012, ECO:0000269|PubMed:9147655}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinal muscular atrophy 2 (SMA2) [MIM:253550]: An autosomal recessive form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. It has intermediate severity, with onset between 6 and 18 months. Patients do not reach the motor milestone of standing, and survive into adulthood. {ECO:0000269|PubMed:10732802, ECO:0000269|PubMed:14715275, ECO:0000269|PubMed:9158159, ECO:0000269|PubMed:9837824}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinal muscular atrophy 3 (SMA3) [MIM:253400]: An autosomal recessive form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Onset is after 18 months. Patients develop ability to stand and walk and survive into adulthood. {ECO:0000269|PubMed:10732817, ECO:0000269|PubMed:14715275, ECO:0000269|PubMed:9158159, ECO:0000269|PubMed:9837824}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinal muscular atrophy 4 (SMA4) [MIM:271150]: An autosomal recessive form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Onset is in adulthood, disease progression is slow, and patients can stand and walk. {ECO:0000269|PubMed:7658877, ECO:0000269|PubMed:8551862}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.131
Essentials
- Essential (CRISPR)
- E
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Medium |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |