rs72544141

Positions:

• chr4-113348277-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001148.6(ANK2):​c.4373A>G​(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:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (1 hom.)
• Consequence: ANK2 NM_001148.6 missense, splice_region
• Scores: Splicing: ADA: 0.7324
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 B:4 O:1
• Conservation: PhyloP100: 9.04

Genes affected

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.01375708).
• BS2: High AC in GnomAd4 at 128 AD gene.

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: 128 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000546 AC: 137 AN: 251086 Hom.: 1 AF XY: 0.000538 AC XY: 73 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000802

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000735 AC: 1074 AN: 1461172 Hom.: 1 Cov.: 30 AF XY: 0.000718 AC XY: 522 AN XY: 726866

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000850

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.000820 AC XY: 61 AN XY: 74422

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000737 Hom.: 0

Bravo AF: 0.00121

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related Pathogenic:2 Uncertain: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:1 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;.;D;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;N
REVEL	Uncertain	0.31
Sift	Benign	0.35	T;T;T;T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T;T;T;T
Polyphen		0.012, 0.016, 0.0010	.;B;.;B;.;.;B;.
Vest4		0.55, 0.44, 0.49, 0.40, 0.46, 0.45
MVP		0.62
MPC		1.0
ClinPred		0.13	T
GERP RS		5.7
Varity_R		0.52
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72544141; hg19: chr4-114269433;