Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_001386166.1(ANK2):c.-58C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 1,614,100 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 4-113336009-C-T is Benign according to our data. Variant chr4-113336009-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113336009-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00254 (387/152282) while in subpopulation AFR AF= 0.00765 (318/41552). AF 95% confidence interval is 0.00696. There are 1 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The vriant affects a non-conserved nucleotide and results in synonymous mutation. Mutation taster predicts a disease causing outcome for this change while 5/5 in silico tools via Alamut predict no impact on splicing. The variant was observed in the large and broad cohorts of the NHLBI-ES and ExAC projects at an allele frequency of 0.15% which greatly exceeds (~150 times) the maximal expected allele frequency of a disease causing ANK2 allele (0.001%), strongly supporting a benign nature for the variant. Based on the high allele frequency in the general population, the variant was classified as Benign. -
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 12, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
ANK2: BP4, BP7 -
not specified Benign:3
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Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Cardiac arrhythmia, ankyrin-B-related Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Dec 05, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Long QT syndrome Benign:1
Jan 11, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Cardiovascular phenotype Benign:1
Aug 31, 2017
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -