SHANK1

protein-coding

SH3 and multiple ankyrin repeat domains 1, the group of PDZ domain containing|Sterile alpha motif domain containing|Ankyrin repeat domain containing

Gene summary

This gene encodes a member of the SHANK (SH3 domain and ankyrin repeat containing) family of proteins. Members of this family act as scaffold proteins that are required for the development and function of neuronal synapses. Deletions in this gene may be associated with autism spectrum disorder in males. [provided by RefSeq, Apr 2016]

MANE transcript

NM_016148.5

Inheritance

ClinVar variants

P:25U:469B:166

Top phenotype

complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr19:50,659,255-50,719,802

External References & Databases

Ensembl (ENSG00000161681)

Transcript & Mutation Effects

hg38 • Region Span ~60.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

autismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*SHANK1* was first reported in relation to autosomal dominant autism spectrum disorder (ASD) in 2012 (Sato et al., PMID: 22503632). The authors reported a male proband with a *de novo* deletion spanning *SHANK1* and *SYT3*, and a multigenerational family with six individuals carrying a deletion of *SHANK1* and *CLEC11A*, in which the males, but not the carrier mothers, had ASD. None of these cases were awarded points in this curation because the deletions encompass other genes. Subsequently, May et al. (2021, PMID: 34113010) reported *de novo* truncating variants in *SHANK1* in six probands with a spectrum of neurodevelopmental disorders, including motor and speech delays, intellectual disability or learning disabilities, ASD, hypotonia, and seizures. At least 9 additional probands with *SHANK1* truncating variants and complex neurodevelopmental disorder, including intellectual disability, developmental delay, ASD, and epilepsy, have been reported in large cohort studies (PMIDs: 27824329, 29100083, 33057194, 34113010, 34374989, 35982160, 36980980). Seven *de novo* truncating variants (nonsense, frameshift, and splice) that have been reported in seven probands in two publications (PMIDs: 27824329, 34113010) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. In addition to the two unaffected deletion carrier mothers mentioned above (PMID: 22503632), a *SHANK1* *de novo* truncating variant was observed in an unaffected male sibling of an ASD proband (PMID: 35982160), suggesting incomplete penetrance. The mechanism of pathogenicity is loss of function (PMID: 34113010). This gene-disease relationship is also supported by experimental evidence, including functional alteration, biochemical function, and animal models. *SHANK1* is a member of the SHANK gene family, which includes *SHANK1*, *SHANK2*, and *SHANK3*, and encodes scaffolding proteins that are enriched in the postsynaptic density of glutamatergic synapses. *SHANK2* and *SHANK3* are also involved in neurodevelopmental disorders associated with ASD and intellectual disability. In summary, there is definitive evidence supporting the relationship between *SHANK1* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 20, 2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SHANK1 variants in ClinVar

17 Conditions Cataloged

Inborn genetic diseasesTotal: 334

not providedTotal: 264

not specifiedTotal: 62

SHANK1-related disorderTotal: 55

Intellectual disabilityTotal: 7

Neurodevelopmental disorderTotal: 3

SHANK1-related Neurodevelopmental DisorderTotal: 3

Complex neurodevelopmental disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016148.5. 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			1 clinvar	101 clinvar	9 clinvar	111
missense		1 clinvar	461 clinvar	52 clinvar	4 clinvar	518
nonsense	6 clinvar	4 clinvar	3 clinvar			13
start loss						0
frameshift	6 clinvar	8 clinvar	2 clinvar			16
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	12	13	469	153	13	660

Highest pathogenic variant AF is 0.000005319254

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016148.5	RefSeq	NP_057232.2	23	MANE Select
ENST00000293441.6	Ensembl	ENSP00000293441.1	23	MANE Select
ENST00000359082.3	Ensembl	ENSP00000351984.2	22	Standard
ENST00000391814.5	Ensembl	ENSP00000375690.1	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutamatergic synapse - Homo sapiens (human)
Neuronal System
Neurexins and neuroligins
Protein-protein interactions at synapses

Biological Process

cytoskeletal anchoring at plasma membrane
synapse assembly
long-term memory
associative learning
adult behavior

Molecular Function

protein binding
protein C-terminus binding
SH3 domain binding
receptor signaling complex scaffold activity
GKAP/Homer scaffold activity

Cellular Component

cytosol
plasma membrane
ionotropic glutamate receptor complex
postsynaptic density
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000293441
Coding exons: 23
Length: 57624
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.64	738	1.07e+3	0.687	0.0000662	13397
Missense (PolyPhen)		63	163.29	0.38582		1768
Synonymous	-0.580	512	496	1.03	0.0000336	4871
Loss of Function	7.07	7	71.5	0.0979	0.00000432	769

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000064	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.;

Recessive Scores

pRec: 0.103

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.309

Gene Damage Prediction

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