GRN

granulin precursor

Basic information

Region (hg38): 17:44345245-44353106

Links

ENSG00000030582 ∙ NCBI:2896 ∙ OMIM:138945 ∙ HGNC:4601 ∙ Uniprot:P28799 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neuronal ceroid lipofuscinosis 11 (Moderate), mode of inheritance: AR
• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (Strong), mode of inheritance: AD
• neuronal ceroid lipofuscinosis 11 (Moderate), mode of inheritance: AR
• neuronal ceroid lipofuscinosis 11 (Supportive), mode of inheritance: AR
• neuronal ceroid lipofuscinosis 11 (Strong), mode of inheritance: AR
• neuronal ceroid lipofuscinosis (Definitive), mode of inheritance: AR
• frontotemporal dementia and/or amyotrophic lateral sclerosis (Definitive), mode of inheritance: AD
• neuronal ceroid lipofuscinosis 11 (Strong), mode of inheritance: AR
• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Frontotemporal lobar degeneration with TDP43 inclusions, GRN-related; Neuronal ceroid lipofuscinosis 11	AD/AR	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	Biochemical; Neurologic; Ophthalmologic	6497355; 9633693; 16862116; 16862115; 16983677; 16401619; 16983685; 16495329; 17436289; 17210807; 18392865; 18543312; 18183624; 18413474; 18703462; 18723524; 19884572; 20142524; 20142525; 22338605; 22366770; 22491866; 22608501; 22647257; 22815225; 22890101; 22906081; 22986778

ClinVar

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

• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;Neuronal ceroid lipofuscinosis 11 (241 variants)
• Neuronal ceroid lipofuscinosis 11;GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (182 variants)
• not provided (178 variants)
• Inborn genetic diseases (97 variants)
• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (85 variants)
• not specified (21 variants)
• Frontotemporal dementia (15 variants)
• GRN-related condition (7 variants)
• Neuronal ceroid lipofuscinosis 11 (5 variants)
• Primary progressive aphasia (3 variants)
• FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS, SUSCEPTIBILITY TO (1 variants)
• Alzheimer disease (1 variants)
• Ischemic stroke (1 variants)
• Amyotrophic lateral sclerosis type 10 (1 variants)
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (1 variants)
• GRN-Related Disorders (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRN 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			7	102	1	110
missense	1		201	7	1	210
nonsense	20	3				23
start loss	2					2
frameshift	41	3	2			46
inframe indel			5			5
splice donor/acceptor (+/-2bp)	13	8	1			22
splice region	1	3	16	14	4	38
non coding			7	35	9	51
Total	77	14	223	144	11

Highest pathogenic variant AF is 0.00000659

Variants in GRN

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

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

Position	Type	Phenotype	Significance	ClinVar
17-44345270-G-T		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions • not specified • Neuronal ceroid lipofuscinosis 11;GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Benign/Likely benign (Sep 01, 2023)
17-44345286-T-G		not specified	Benign (May 25, 2017)
17-44345297-C-G		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions • not specified	Likely benign (Nov 24, 2020)
17-44345304-T-C		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Benign (Jan 13, 2018)
17-44345320-C-T		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Uncertain significance (Apr 27, 2017)
17-44345328-G-C			Likely benign (Aug 16, 2017)
17-44345337-A-C		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Uncertain significance (Apr 27, 2017)
17-44345337-A-G			Likely pathogenic (Mar 01, 2018)
17-44345337-A-T			not provided (-)
17-44345339-G-A		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;Neuronal ceroid lipofuscinosis 11	Uncertain significance (Apr 12, 2022)
17-44345339-G-C		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Pathogenic (Oct 01, 2007)
17-44345347-C-A		GRN-related disorder	Likely benign (Apr 15, 2019)
17-44345380-G-T		Neuronal ceroid lipofuscinosis 11;GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Benign (Jan 31, 2021)
17-44345383-C-CG			Benign (May 23, 2021)
17-44345570-G-A			Likely benign (Oct 11, 2021)
17-44348838-C-G			Benign (Aug 31, 2018)
17-44349083-A-G			Likely benign (Feb 26, 2020)
17-44349165-A-G		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;Neuronal ceroid lipofuscinosis 11	Pathogenic (Oct 27, 2021)
17-44349166-T-C		Neuronal ceroid lipofuscinosis 11;GRN-related frontotemporal lobar degeneration with Tdp43 inclusions • GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Pathogenic (Feb 22, 2023)
17-44349167-G-A		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Pathogenic (Aug 24, 2006)
17-44349169-G-A		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;Neuronal ceroid lipofuscinosis 11	Pathogenic (Nov 01, 2023)
17-44349170-G-A			Likely pathogenic (Dec 01, 2016)
17-44349171-A-G		Neuronal ceroid lipofuscinosis 11	Uncertain significance (Jan 01, 2016)
17-44349172-C-G		GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;Neuronal ceroid lipofuscinosis 11	Uncertain significance (Jul 24, 2019)
17-44349172-C-T		Inborn genetic diseases • GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;Neuronal ceroid lipofuscinosis 11	Uncertain significance (Mar 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRN	protein_coding	protein_coding	ENST00000053867	12	7857

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0697	0.930	125720	0	28	125748	0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.275	341	356	0.959	0.0000234	3881
Missense in Polyphen		125	126.08	0.99141		1498
Synonymous	-1.25	165	146	1.13	0.0000108	1135
Loss of Function	3.71	8	29.9	0.268	0.00000157	325

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000233	0.000231
European (Non-Finnish)	0.000150	0.000132
Middle Eastern	0.00	0.00
South Asian	0.000163	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Granulins have possible cytokine-like activity. They may play a role in inflammation, wound repair, and tissue remodeling.
• Disease: DISEASE: Ubiquitin-positive frontotemporal dementia (UP-FTD) [MIM:607485]: Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. It is an autosomal dominant neurodegenerative disease. {ECO:0000269|PubMed:16862116, ECO:0000269|PubMed:16983685, ECO:0000269|PubMed:18183624}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ceroid lipofuscinosis, neuronal, 11 (CLN11) [MIM:614706]: A form of neuronal ceroid lipofuscinosis characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material. {ECO:0000269|PubMed:22608501}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Integrated Breast Cancer Pathway;Neutrophil degranulation;Innate Immune System;Immune System (Consensus)

Recessive Scores

• pRec: 0.430

Intolerance Scores

• loftool: 0.597
• rvis_EVS: -0.46
• rvis_percentile_EVS: 23.66

Haploinsufficiency Scores

• pHI: 0.118
• hipred: N
• hipred_score: 0.474
• ghis: 0.487

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.802

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Grn
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; pigmentation phenotype; cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: grna
• Affected structure: CaP motoneuron
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: signal transduction;regulation of signaling receptor activity;neutrophil degranulation
• Cellular component: extracellular region;lysosome;endosome;endoplasmic reticulum;azurophil granule lumen;extracellular exosome
• Molecular function: RNA binding;cytokine activity;protein binding;growth factor activity