Submissions for variant NM_001148.6(ANK2):c.11859+2T>G

dbSNP: rs2154075277

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002337819	SCV002639527	uncertain significance	Cardiovascular phenotype	2021-04-21	criteria provided, single submitter	clinical testing	The c.11859+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 45 in the ANK2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of ANK2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002463200	SCV002757326	likely pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003408243	SCV004113048	uncertain significance	ANK2-related disorder	2022-11-02	criteria provided, single submitter	clinical testing	The ANK2 c.11859+2T>G variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775964	SCV004625731	likely pathogenic	Long QT syndrome	2024-04-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 45 of the ANK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ANK2 are known to be pathogenic (PMID: 37195288). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1743112). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.