rs72544141
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2
The NM_001148.6(ANK2):āc.4373A>Gā(p.Glu1458Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,613,402 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001148.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANK2 | NM_001148.6 | c.4373A>G | p.Glu1458Gly | missense_variant, splice_region_variant | 36/46 | ENST00000357077.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANK2 | ENST00000357077.9 | c.4373A>G | p.Glu1458Gly | missense_variant, splice_region_variant | 36/46 | 1 | NM_001148.6 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000841 AC: 128AN: 152112Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000546 AC: 137AN: 251086Hom.: 1 AF XY: 0.000538 AC XY: 73AN XY: 135680
GnomAD4 exome AF: 0.000735 AC: 1074AN: 1461172Hom.: 1 Cov.: 30 AF XY: 0.000718 AC XY: 522AN XY: 726866
GnomAD4 genome ? AF: 0.000841 AC: 128AN: 152230Hom.: 1 Cov.: 32 AF XY: 0.000820 AC XY: 61AN XY: 74422
ClinVar
Submissions by phenotype
Cardiac arrhythmia, ankyrin-B-related Pathogenic:2Uncertain:1
Pathogenic, flagged submission | literature only | OMIM | Jun 15, 2004 | - - |
Uncertain significance, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 16, 2024 | - - |
Likely pathogenic, flagged submission | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 22, 2014 | The p.Glu1458Gly variant (also referred to as p.Glu1425Gly) has been identified in >20 affected members of a large kindred with autosomal dominant long QT syndrome (Mohler 2003). It has been identified in an unaffected individual whose three siblings died suddenly at a young age (Mohler 2004). It has also been identified in 0.06% (41/67458) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72544141). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro and in vivo functional studies in mice provide some evidence that the p.Glu1458Gly variant may impact protein function (Mohler 2003, Mohler 2004, Le Scouarnec 2008). In p.Glu1458Gly variant is likely pathogenic. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2023 | Reported in several individuals with sudden death/SIDS (PMID: 26350513, 27930701, 29247119, 28074886) and in association with HCM (PMID: 23396983, 25351510), although additional cardiogenetic variants were identified in some of these probands; Reported in several individuals without a known history of cardiovascular disease (PMID: 23861362, 26159999, 28654958, 29431110); Identified as secondary finding in a cohort of patients with intellectual disability or developmental delay referred for WES/WGS who was reported to have a clinical diagnosis of HCM and arrhythmia (PMID: 29790872); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated this variant results in abnormal Ca2+ signaling in mouse cardiomyocytes, and mice heterozygous for this variant had a high incidence of sudden death after exercise and exposure to epinephrine (PMID: 12571597, 17242276); This variant is associated with the following publications: (PMID: 17242276, 23396983, 26159999, 15178757, 7485162, 29247119, 28880023, 27930701, 28654958, 28074886, 18832177, 26220970, 26350513, 19394342, 29431110, 20724725, 22581653, 28988457, 25351510, 32164423, 29198934, 35990955, 12571597, 29790872, 23861362) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | May 28, 2020 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 01, 2018 | The ANK2 c.4373A>G; p.Glu1458Gly variant (rs72544141), also known as p.Glu1425Gly, is reported in the literature in individuals affected with Long QT syndrome, sinus node dysfunction, arrhythmia, sudden unexplained death, and hypertrophic cardiomyopathy (Hertz 2016, Le Scouarnec 2008, Lin 2017. Lopes 2013, Mohler 2003, Neubauer 2017). In one large family, this variant segregated with long QT syndrome and sinus node dysfunction in more than 20 affected individuals and was not observed in any unaffected individuals (Le Scouarnec 2008, Mohler 2003). However, this variant was also observed in a healthy individual with normal QT interval (Mohler 2004), and it was not significantly associated with longer QT interval in a large Dutch cohort (Ghouse 2015). Further, the p.Glu1458Gly variant is found in the Latino population with an overall allele frequency of 0.11% (38/24226 alleles, including one homozygote) in the Genome Aggregation Database, and this population frequency exceeds the estimated prevalence of Long QT syndrome at 1 in 2000 (Lin 2017). In mouse cardiomyocytes lacking one copy of ANK2, transfection of the p.Glu1458Gly variant fails to rescue decreased spontaneous contraction rate to the same extent as wildtype protein (Mohler 2003, Mohler 2007). The glutamate at codon 1458 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the p.Glu1458Gly variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Hertz CL et al. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Hum Genet. 2016 Jun;24(6):817-22. Le Scouarnec S et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15617-22. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6). Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Mohler PJ et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. Mohler PJ et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9. Mohler PJ et al. Defining the cellular phenotype of ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation. 2007 Jan 30;115(4):432-41. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 Apr;25(4):404-409. " - |
Long QT syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Long QT syndrome 4 Pathogenic:1
Pathogenic, flagged submission | literature only | OMIM | Jun 15, 2004 | - - |
Conduction disorder of the heart Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2021 | 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. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12571597;PMID:15178757;PMID:18832177). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at