ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 4q25-q26
  • GRCh37/hg19 chr4: 113,739,239-114,304,896
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr4: 112,705,622-113,383,736
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000004.11) (NC_000004.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
25363760 De Rubeis et al. 2014 analyzed rare coding variation using exome sequencing results from 3871 autism cases and 9937 ancestry-matched or parental controls. In Supplemental Table 3, Individual DEASD_0140_001 was found to have a de novo nonsense variant in ANK2; this individual was also found to have de novo missense variants in two other genes. No detailed phenotypic information was available. Two other individuals, UK10K_SKUSE5080174 and 10C105731, were found to have de novo missense variants in ANK2; the former patient also had a de novo nonsense variant in another gene. Additionally, the authors noted a multi-exon intragenic deletion within ANK2 (01HI2071A) of unknown inheritance. PMID: 28263302 C Yuen RK et. al., 2017 performed WGS of 5,205 samples from families with ASD. Patient AU3728301 has a de novo exonic deletion in ANK2. AU3645301 has a paternal inherited deletion. PMID: 30564305. Guo et al ? In 3120 total ASD patients, one de novo nonsense variant (p.R994X, proband ID M32110). PMID: 28554332. Bowling et al ? one de novo frameshift deletion insertion. PMID: 25356970. Farwell et al - one de novo frameshift.
22542183 Iossifov et al. 2012 report on exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling (Simons Simplex Collection). A de novo nonsense variant in ANK2 was identified in the affected individual in Family 12645.
25363768 Iossifov et al. 2014 expand on their 2012 work by reporting on exome sequencing in 2500 autism simplex families. In addition to Family 12645 (mentioned in the 2012 article above), one additional de novo nonsense variant was detected in ANK2 (Family 14256). There was also a de novo frameshift variant (Family 13768).

Haploinsufficiency phenotype comments:

Across the publications listed above, there have been at least 4 de novo nonsense variants, 3 de novo frameshift variants, and one de novo exonic deletion in ANK2; other de novo missense variants and other variants of unknown inheritance have been reported in other publications studying autism cohorts. Variation in ANK2 has also been implicated in Long QT syndrome (PMIDs: 17242276,12571597, 15178757, and others). Variants reported to date associated with this phenotype have been missense, though functional studies suggest that they act as loss of function. Reported variants appear to cluster near the "death" and C-terminal domains (PMID: 17242276). Mice heterozygous for a null mutation in ankyrin-B display arrhythmia similar to humans (PMID:12571597). Several copy number losses (of varying sizes) including ANK2 (and multiple other genes) have been reported in both DECIPHER and ClinVar; the phenotype information provided is varied and is not overwhelminingly indicative of either autism or cardiac phenotypes. This information must be considered carefully, as it is unknown whether or not those particular phenotypes were evaluated and/or documented in each individual case. Additional information is needed to understand the complete phenotypic spectrum associated with copy number loss of ANK2.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity