SHANK2

Chr 11

SH3 and multiple ankyrin repeat domains 2

Also known as: AUTS17, CORTBP1, CTTNBP1, ProSAP1, SHANK, SPANK-3

NCBI Gene: 22941 ENSG00000162105 UniProt: Q9UPX8

The protein functions as a molecular scaffold in the postsynaptic density of excitatory synapses, containing multiple protein-protein interaction domains including ankyrin repeats, SH3, and PDZ domains. Mutations cause autism spectrum disorder with autosomal dominant inheritance. The pathogenic mechanism involves disruption of synaptic scaffolding and altered protein interactions at excitatory synapses.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, and an SH3 domain. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. Alterations in the encoded protein may be associated with susceptibility to autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAutism 17

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2019
Strong · autism, susceptibility to, 17 · AD · Labcorp Genetics (formerly Invitae)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — SHANK2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.000

Z-score 5.51

OE 0.33 (0.24–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.32Z-score

OE missense 0.81 (0.76–0.85)

923 obs / 1144.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.33 (0.24–0.46)

0≤0.351.4

Missense OE?0.81 (0.76–0.85)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 26 / 78.8Missense obs/exp: 923 / 1144.3Syn Z: -0.22

Background carrier burden — how many people carry a rare variant somewhere in SHANK2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

2,273 rare PASS variants

Rare truncating (LoF)

1 in 980

111 rare PASS variants

Rare synonymous (reference)

1 in 29

1,120 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SHANK2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 28	1 in 1,000
South Asian	~43k	1 in 20	1 in 890
Remaining (unassigned)	~30k	1 in 22	1 in 3,700
European (Finnish)	~27k	1 in 67	1 in 940
Admixed American	~22k	1 in 22	1 in 800
African / African American	~21k	1 in 20	1 in 900
East Asian	~20k	1 in 23	1 in 2,300
Ashkenazi Jewish	~13k	1 in 74	1 in 870
Middle Eastern	~2,884	1 in 23	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 24 coding exons well covered in gnomAD exomes; exons 9, 10, 11, 12, 13 and 2 more poorly covered; exon 6 marginal. Genomes: all 24.? see exons ↓