SMCR8

SMCR8-C9orf72 complex subunit, the group of DENN domain containing|SWC tripartite complex

Basic information

Region (hg38): 17:18315293-18328056

Links

ENSG00000176994 ∙ NCBI:140775 ∙ OMIM:617074 ∙ HGNC:17921 ∙ Uniprot:Q8TEV9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMCR8 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMCR8 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				2		2
missense			59	1	1	61
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	59	3	1

Variants in SMCR8

This is a list of pathogenic ClinVar variants found in the SMCR8 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-18315855-T-A		not specified	Uncertain significance (Oct 25, 2023)
17-18315881-C-T		not specified	Uncertain significance (Oct 30, 2023)
17-18315886-C-G			Uncertain significance (Sep 01, 2023)
17-18315926-C-T		not specified	Uncertain significance (Jun 23, 2023)
17-18315967-A-C		not specified	Uncertain significance (Jun 27, 2022)
17-18316003-T-G		not specified	Uncertain significance (Mar 17, 2023)
17-18316019-A-G		not specified	Uncertain significance (May 11, 2022)
17-18316102-G-T		not specified	Uncertain significance (Oct 06, 2022)
17-18316110-T-C			Likely benign (May 01, 2022)
17-18316127-C-T		not specified	Uncertain significance (Jun 03, 2024)
17-18316141-G-T		not specified	Uncertain significance (Aug 08, 2023)
17-18316196-T-C		not specified	Uncertain significance (Nov 09, 2023)
17-18316224-G-T		not specified	Uncertain significance (Jul 06, 2021)
17-18316253-T-C		not specified	Uncertain significance (Oct 03, 2023)
17-18316293-G-A			Likely benign (May 01, 2022)
17-18316507-G-C		not specified	Uncertain significance (Apr 27, 2022)
17-18316525-C-A		not specified	Uncertain significance (Jun 21, 2022)
17-18316558-C-T		not specified	Uncertain significance (Jun 12, 2023)
17-18316565-G-A		not specified	Uncertain significance (Dec 03, 2021)
17-18316627-C-G		not specified	Uncertain significance (Jun 10, 2024)
17-18316687-C-G		not specified	Uncertain significance (Sep 27, 2021)
17-18316687-C-T		not specified	Uncertain significance (Jan 25, 2023)
17-18316817-A-G		not specified	Uncertain significance (Dec 11, 2023)
17-18316862-A-T		not specified	Uncertain significance (Aug 12, 2021)
17-18316888-A-G		not specified	Uncertain significance (Aug 02, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMCR8	protein_coding	protein_coding	ENST00000406438	2	7894

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00160	0.997	125726	0	22	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.03	574	509	1.13	0.0000285	6206
Missense in Polyphen		203	214.79	0.94512		2688
Synonymous	-3.23	271	211	1.28	0.0000124	1855
Loss of Function	2.84	9	24.0	0.375	0.00000113	334

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000210	0.000210
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.00	0.00
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:20562859, PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:20562859, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27617292, PubMed:28195531). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131, PubMed:28195531). In addition to its activity in the cytoplasm within the C9orf72-SMCR8 complex, SMCR8 also localizes in the nucleus, where it associates with chromatin and negatively regulates expression of suppresses ULK1 and WIPI2 genes (PubMed:28195531). {ECO:0000269|PubMed:20562859, ECO:0000269|PubMed:27103069, ECO:0000269|PubMed:27193190, ECO:0000269|PubMed:27559131, ECO:0000269|PubMed:27617292, ECO:0000269|PubMed:28195531}.

Intolerance Scores

• loftool: 0.237
• rvis_EVS: -0.79
• rvis_percentile_EVS: 12.62

Haploinsufficiency Scores

• pHI: 0.191
• hipred: Y
• hipred_score: 0.530
• ghis: 0.623

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.871

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Smcr8
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: negative regulation of protein kinase activity;autophagy;regulation of autophagy;negative regulation of gene expression;negative regulation of macroautophagy;positive regulation of TOR signaling;positive regulation of autophagosome maturation;negative regulation of autophagosome assembly;regulation of TORC1 signaling
• Cellular component: chromatin;nucleoplasm;cytoplasm;guanyl-nucleotide exchange factor complex;Atg1/ULK1 kinase complex
• Molecular function: protein kinase inhibitor activity;protein binding;Rab guanyl-nucleotide exchange factor activity;protein kinase binding