ANK2

Gene Facts

• HGNC Symbol: ANK2 (HGNC:493)
• HGNC Name: ankyrin 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: LQT4
• Alias symbols: FAP87, CFAP87
• %HI: 24.11
• pLI: 1
• LOEUF: 0.27
• Cytoband: 4q25-q26
• Genomic Coordinates:

  GRCh37/hg19:	chr4:113626778-114304892
  GRCh38/hg38:	chr4:112705622-113383736

• MANE Select Transcript: NM_001148.6 ENST00000357077.9
• Function: Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells. In skeletal muscle, required for proper localization of DMD and DCTN4 and for the formation and/or stability of a special subset of microtubules associated with costameres and neuromuscular junctions. In cardiomyocytes, required for coordinate assembly of Na/Ca exchanger, SLC8A1/NCX1, Na/K ATPases ATP1A1 ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-22532
• ClinGen Curation ID: CCID:006663
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 05/22/2019

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• complex neurodevelopmental disorder

HI Evidence

• PUBMED: 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.
• PUBMED: 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.
• PUBMED: 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).

• HI Evidence 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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity