rs746436835

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001148.6(ANK2):c.2063T>A(p.Ile688Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.48

Publications

2 publications found

Variant links:

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]

ANK2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P
cardiac arrhythmia, ankyrin-B-related
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ANK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6 link	c.2063T>A	p.Ile688Asn	missense_variant	Exon 18 of 46	ENST00000357077.9	NP_001139.3	Q01484-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 link	c.2063T>A	p.Ile688Asn	missense_variant	Exon 18 of 46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251066

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111906

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 21, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

The patient is a 13-year-old female with a QTc of up to 509 msec on EKG. She had genetic testing for LQTS with the Invitae laboratory. The following 17 genes were evaluated for sequence changes and exonic deletions/duplications: AKAP9, ANK2, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN. The lab reported two variants: â€¢ p.Arg366Gln (R366Q; c.1097G>A) in the KCNQ1 gene (pathogenic, and diagnostic of LQTS type 1) â€¢ p.Ile688Asn (I688N; c.2063T>A) in the ANK2 gene p.Ile688Asn (I688N; c.2063T>A) in exon 18 of the ANK2 gene (NM_001148.4; ENST00000357077.8) Chromosome location: 4:114204012 T / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not been reported in the literature in association with disease, but it is present in population databasesâ€”exclusively in people with this patientâ€™s ethnicity. For this reason, we think it is more likely to be benign. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Isoleucine with a polar Asparagine. Isoleucine at this location is not conserved across vertebrate species, and may be replaced by another nonpolar amino acid such as Valine or Alanine. There are no clearly Pathogenic or Likely Pathogenic variants listed in ClinVar within 10 amino acids of this codon as of 4/21/2017. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant was reported online in 7 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 7/9,432 East Asians (for the highest allele frequency: 0.037%). It is not reported in any other ancestry group. Our patientâ€™s ancestry is from Vietnam. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. (There is 1 Caucasian individual in gnomAD with another variant at this site: p.Ile688Val.) -

Long QT syndrome

Uncertain:1

Aug 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 688 of the ANK2 protein (p.Ile688Asn). This variant is present in population databases (rs746436835, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of neurodevelopmental disorder (PMID: 30564305, 33004838). This variant is also known as 4:114204012T>A and c.2000T>A (p.Ile667Asn). ClinVar contains an entry for this variant (Variation ID: 264395). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ANK2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Oct 03, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I688N variant (also known as c.2063T>A), located in coding exon 18 of the ANK2 gene, results from a T to A substitution at nucleotide position 2063. The isoleucine at codon 688 is replaced by asparagine, an amino acid with dissimilar properties. Based on data from ExAC, the A allele has an overall frequency of approximately 0.001% (2/120940). The highest observed frequency was 0.02% (2/8632) of East Asian alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed September 30, 2015]). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;T;.;T;.;D;T;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.041

MutationAssessor

Pathogenic

3.4

.;.;.;.;M;M;.;.

PhyloP100

3.5

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;D;D;.

REVEL

Uncertain

0.51

Sift

Benign

0.076

T;D;D;T;D;D;D;.

Sift4G

Benign

0.064

T;D;D;D;D;D;D;D

Polyphen

0.82, 0.98, 1.0

.;.;P;.;D;D;.;.

Vest4

0.81, 0.78, 0.81, 0.87

MutPred

0.72

.;.;.;.;Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;

MVP

0.69

MPC

2.0

ClinPred

0.94

GERP RS

5.1

Varity_R

0.90

gMVP

0.67

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over