rs45454496

chr4-113373381-G-Achr4-113373381-G-Cchr4-113373381-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001148.6(ANK2):c.11791G>A(p.Glu3931Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,614,190 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (21 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13 O:1
• Conservation: PhyloP100: 2.07

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.027564794).
• BP6: Variant 4-113373381-G-A is Benign according to our data. Variant chr4-113373381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 18060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113373381-G-A is described in Lovd as [Likely_benign]. Variant chr4-113373381-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00355 (5187/1461870) while in subpopulation MID AF= 0.00537 (31/5768). AF 95% confidence interval is 0.00389. There are 21 homozygotes in gnomad4_exome. There are 2546 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 348 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.11791G>A	p.Glu3931Lys	missense_variant	45/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.11791G>A	p.Glu3931Lys	missense_variant	45/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00283 AC: 710 AN: 251200 Hom.: 6 AF XY: 0.00286 AC XY: 388 AN XY: 135758

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00355 AC: 5187 AN: 1461870 Hom.: 21 Cov.: 33 AF XY: 0.00350 AC XY: 2546 AN XY: 727240

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00386

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74498

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00345

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00431 Hom.: 7

Bravo AF: 0.00261

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00267 AC: 324

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jun 15, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ANK2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2016	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size acidic Glutamate (E) with a large size and basic Lysine (K). 2/5 in silico tool predict deleterious outcome for this change. It was found in the large and broad cohorts of NHLBI-ESP; ExAC and 1000G projects as well as in healthy control individuals in disease specific publications at a composite allele frequency of 0.26.8% which greatly exceeds the maximal allele frequency of a disease causing ANK2 allele (0.001%) indicating a benign impact. In addition, there are three homozygous individuals reported in ExAC further supporting a non-disease causing outcome. Variant was found in ARTHY patients however because of the lack of familial segregation data or comprehensive ANK2 testing these studies do not permit establishment of a cause-effect relationship between the variant and ARTHY (Mohler_PNAS_2004; Mohler_Circ_2007). One research group investigated the impact of the variant on the function of the protein and concluded that overall, the variant has negligible loss of function impact on the protein (Mohler_Circulation_2007). Clinical diagnostic centers classify variant as Benign/Likely Benign via ClinVar without evidence to independently evaluate. Taken together, evidences support a benign nature for the variant, therefore variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 25, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -

Cardiac arrhythmia Benign:1 Other:1

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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 Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

ANK2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ventricular fibrillation Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Oct 02, 2018

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.058
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.028	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	0.0032	A;A;A;A;A;A
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N;N;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.19	T;T;D;D;T;D;D
Sift4G	Benign	0.19	T;T;D;D;T;T;T
Polyphen		0.76	P;P;.;.;B;.;.
Vest4		0.20
MVP		0.88
MPC		0.17
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs45454496; hg19: chr4-114294537; COSMIC: COSV99053389;